Illumination of an eye fundus using non-scanning coherent light

ABSTRACT

Imaging various regions of the eye is important for both clinical diagnostic and treatment purposes as well as for scientific research. Diagnosis of a number of clinical conditions relies on imaging of the various tissues of the eye. The subject technology describes a method and apparatus for imaging the eye using off-center illumination in a manner that avoids light striking the anterior surfaces of the eye at or near a center of the optical axis, thereby reducing reflections traveling back along an imaging light path, while also providing substantially uniform illumination of a region of interest of the fundus.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to P.C.T. Application No.PCT/US2021/021695, filed Mar. 10, 2021, entitled “ILLUMINATION OF AN EYEFUNDUS USING NON-SCANNING COHERENT LIGHT”, which claims priority to U.S.Provisional Application No. 62/989,224, filed Mar. 13, 2020, entitled“ILLUMINATION OF AN EYE FUNDUS USING NON-SCANNING COHERENT LIGHT.” Theentire contents of each are incorporated herein by reference for allpurposes.

GOVERNMENT LICENSE RIGHTS

This invention utilized government support under grant 2R44AG048758awarded by the National Institute on Aging (of the National Institutesof Health). The government has certain rights in the invention.

FIELD

The subject technology relates to imaging regions of tissue. Inparticular, the subject technology relates to illuminating and acquiringimages of a fundus of an eye.

BACKGROUND

Imaging the internal regions of the eye is important for both clinicaldiagnostic and treatment purposes as well as for scientific research.Diagnosis of a number of clinical conditions (e.g., diabetic retinopathy(DR), hypertensive retinopathy (RR), age related macular degeneration(AMD), retinopathy of prematurity (ROP), retinal detachment, glaucoma,cataract, and various types of neovascularization pathologies in thechoroid (CNV), cornea and retina) relies on imaging appropriately theretina, choroid, the cornea, the sclera, or the eye lens, includingimaging specific aspects of each of these tissues (e.g., blood, bloodvessels, exudates, and other anatomical and physiological features). Anumber of these pathophysiologies are gradual-that is, these disordersdevelop over time-making a strong case for timely diagnosis andmanagement. For example, unmanaged diabetes and DR leads toproliferation of blood vessels in the retina, blood leakage into the eyeand eventually, loss of vision. Thus, not only does retinal imaging havea role in detecting the evidence of a pathophysiology, but also indiagnosing its severity. Early diagnosis through routine monitoring isimportant in disease management and, hence, eye screening is becoming anincreasingly important aspect in primary care.

In addition to these ophthalmic diseases, imaging of the blood vesselsof ophthalmic tissue can be used to detect non-ophthalmic diseases orconditions. These non-ophthalmic disease or conditions can beorgan-specific or systemic. For example, reports in literature have alsoindicated that early signs of brain disorders are also manifested in theretina. Thus, imaging the retina can be used for early diagnosis or riskassessment of conditions like stroke and other types of brain lesions.Similarly, systemic disease (e.g., heart disease or diabetes) can bediagnosed and monitored based on an evaluation of the retinal bloodvessels.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of components of an OID system configured foroff-axis illumination of an eye.

FIG. 2 illustrates light paths from a coherent light source of an OID toa fundus of an eye, according to a first example implementation of anOID system configured for off-axis illumination of an eye.

FIG. 3A illustrates a coherent light beam exiting the objective lens ofan OID of any of the preceding embodiments, according to an exampleimplementation.

FIG. 3B illustrates the coherent light exiting the objective lens of theOID, passing through the cornea, and illuminating the fundus, accordingto an example implementation.

FIG. 3C shows results of a simulation of a coherent light beam from anOID incident on the cornea, according to an example implementation.

FIG. 3D shows results of a simulation of coherent light from the OIDincident on a retina, according to an example implementation.

FIG. 3E illustrates another configuration in which the coherent lightbeam may exit the objective lens of an OID to illuminate a substantiallylarger field of view.

FIG. 4 illustrates light paths from a coherent light source of an OID toa fundus of an eye, according to a second example implementation of anOID system configured for off-axis illumination of an eye.

FIG. 5 illustrates an OID with an incoherent light source, according toan example implementation.

FIG. 6 illustrates light paths in the OID 400 of FIG. 4 , according toan example implementation.

FIG. 7 illustrates an OID with an internal gaze fixation target forholding a patient's gaze steady during imaging, according to an exampleimplementation.

FIG. 8 illustrates light paths in an OID with a gaze fixation target foruse in fixating a patient's eye and lens during imaging, according to anexample implementation.

FIG. 9 illustrates light paths from a coherent light source of an OID,through cylindrical lenses to a fundus of an eye, according to anexample implementation of an OID system configured for off-axisillumination of an eye.

FIG. 10 is a schematic of the electrical components of the OID.

FIG. 11 shows a flowchart illustrating an example method for off-axisillumination of an eye, according to an example implementation.

DETAILED DESCRIPTION

The subject technology describes a method and apparatus for imaging ofthe back of the eye (i.e., the retina and/or the choroid) usingillumination from at least one non-scanning coherent light source. Theapparatus, embodied as an ophthalmic imaging device (called “OID”hereafter), may use coherent illumination that is generated by any typeof laser source, and any type of camera to acquire image data. The OIDincludes a method and apparatus for illuminating the back of the eyeafter travelling through the pupil of the eye while reducing the amountof illuminating light that reaches the camera after bouncing back fromthe anterior structures of the eye.

Additional illumination modalities may be used to enable additionalimaging modalities. For example, imaging may be carried out undercoherent and incoherent illumination, the timing of which can becontrolled for the desired imaging technique or two types. The coherentillumination may comprise light from different sources that aredifferent in at least one property such as wavelength. Coherentillumination means the degree of coherence of the emitted optical beamis high (e.g., green, red, blue, or near infrared laser) and includes,among other things, various types of lasers including diode lasers, gaslasers, and vertical cavity surface emitting lasers (VCSEL). Incoherentillumination means the degree of coherence of the emitted optical beamis low (e.g., white or spectrally filtered light from a light emittingdiode (LED) or a halogen lamp). Use of multiple illumination modalitiespermits the OID to capture one or more of reflectance images, absorptionspectroscopic images, fluorescence images, and LSCI images with orwithout mydriatic agents.

A number of imaging modalities have been developed that may be ofrelevance for ophthalmic imaging. These include:

(a) Laser speckle contrast imaging. When images are acquired undercoherent (i.e., laser) illumination through an appropriately sizedaperture, speckle patterns are formed. The blurring of speckle patternsdue to motion can be mathematically estimated using a metric calledspeckle contrast, defined as the ratio of standard deviation of pixelintensities to the mean value of pixel intensities within a specifiedneighborhood of every pixel under consideration in the stack of images.The said neighborhood may be of different types and lie in thespatio-temporal domain, as described in Rege A, Senarathna J, Li N,Thakor N V (2012) “Anisotropic processing of laser speckle imagesimproves spatiotemporal resolution”, IEEE Trans Biomed Engr, vol. 59,no.5, pp. 1272-1280.

(b) Spectroscopic imaging. When images acquired under differentillumination wavelengths are compared, it is possible to highlightfeatures based on differential absorption, transmission, and reflectionof light by different tissue/cell types. For example, differentialanalysis under near-infrared and green light can distinguish betweenoxygenated and deoxygenated blood.

(c) Reflectance imaging. This imaging mode is equivalent tophotographing the eye under illumination that is similar to ambientlight (e.g., light from a flashlight, light from a halogen lamp, etc.).These images also contain information analogous to spectroscopic images,since white light intrinsically contains multiple wavelengths of light.Oxygenated blood (in arteries under normal conditions) appears faint ona grayscale image obtained under white light illumination, whiledeoxygenated blood (in veins under normal conditions) appear darker.

(d) Fluorescence imaging. If a fluorescent dye is injected in the bloodvessels, then high contrast images of blood vessels could be obtainedusing appropriate illumination wavelengths and optical filters.

Imaging the retina and/or the choroid poses a number of technical andpractical challenges:

(a) Given the constraints placed by motion artifact on the cameraexposure time in non-stabilized photography, ambient light does notprovide adequate illumination for photographing the retina. Very littleamount of light is captured by the camera sensor within the smallexposure time, limiting its ability to achieve high contrast betweenretinal features. Thus, additional illumination from an external lightsource is generally needed.

(b) The geometry of the eye—specifically, the location of the retina,the pupil (and iris), the cornea and lens—does not provide enough leewayfor the illumination and imaging paths to be along significantlydifferent directions. This problem has been partially solved in the pastusing an optical assembly known as a fundus camera. However, the funduscamera cannot perform laser speckle contrast imaging, a method ofimaging blood vessels and blood flow.

(c) Incidence of the illuminating light, especially coherent light(i.e., laser) on the retina may be harmful, thus placing a stringentconstraint on the amount of energy that can be delivered to the retinato provide illumination for imaging purpose. Conventional retinalimagers that use lasers (e.g., scanning laser ophthalmoscopes) ensurethrough scanning that the laser illuminates a small region of interest(ROI) for a very short period of time, thus restricting the energydelivered to the retina despite using a beam of high power andintensity. Laser speckle contrast imaging (LSCI) involves simultaneousillumination of a field of view (FOV) as opposed to spot illuminationand scanning—for longer periods of time in comparison to priorlaser-based retinal imaging techniques. The overall illumination timecould be as long as 10 seconds. Thus, a low-power laser whose power maybe duly attenuated further must be used; and the activation anddeactivation of the laser module must be controlled using a mechanicalshutter or an electronic switch.

(d) Current retinal imagers place a significant socio-economic burden onits use. The high cost of individual components that make up the retinalimager, makes the overall system expensive. Combining the cost of thedevice with the additional cost of the eye-care specialists required toperform the procedure drives up the cost of eye exams and overallhealthcare expenditures. Further, most retinal imagers requirechemically-induced pupil dilation to capture a large FOV, which makestheir use complicated and inconvenient.

In some embodiments, the OID can be configured with an illuminationscheme that provides for off-center transmission of light through thecornea and lens. Providing illumination light along an optical axis ofthe OID may cause the illumination light to strike the cornea and/orlens at an angle normal to their surface such that the light maypartially reflect back along the optical axis towards the imagingoptics, creating artifacts or otherwise interfering with imaging of thefundus. Accordingly, this disclosure describes optics that can beemployed to transmit light through the cornea and lens while reducingthe amount of light striking the cornea and lens on or near the opticalaxis. Light can be transmitted to and through the cornea and eye lens ina number of shapes including shapes that are substantially annular (ringshape) or polygons on either side of the optical axis while avoidinglight striking the cornea and/or lens on or near the optical axis atangles normal to the surfaces of the lens and cornea. Therefore,off-center transmission of light, in this context, implies that thelight is either generally directed towards the cornea along an axis isnot aligned with the optical axis of the eye, or substantially annularsuch that irrespective of the relative orientations of the illuminationaxis and the optical axis of the eye, the illumination beam does notsignificantly illuminate the region of the cornea that would reflectlight back to the camera.

In the case of incoherent light illumination, due to its tendency todiffuse more than coherent light, preventing light from striking thecornea and lens on or near the optical axis can sometimes be achieved bysimply introducing an obstacle somewhere along the optical axis of thepath of the light between the incoherent light source and the lens. Forexample, an image of the round obstacle can be focused on the cornea asa dark disk in the center of the cornea surrounded by a bright ring.Once the ring of incoherent light passes through the cornea and lens, itwill tend to diffuse as it passes through the eye and illuminate thefundus at least somewhat uniformly. Incoherent light, however, is notsuitable for performing certain types of imaging of the fundus,including laser speckle contrast imaging (LSCI), which requires coherentlight.

With coherent light, however, simply introducing an obstacle along theoptical axis is not sufficient to block light from striking the corneaon axis while also adequately illuminating the fundus substantiallyuniformly across a field of view. Rather, when striking the cornea, thecoherent light will tend to reproduce the shape of the obstacle, whetherannular, polygonal, or some other shape.

This disclosure therefore proposes several techniques for transmittinglight to the eye in a manner that avoids light striking the eye alongthe optical axis, thereby reducing reflections traveling back along animaging light path, while also providing substantially uniformillumination of a region of interest of the fundus. In some embodiments,an OID can include one or more axicon lenses configured to shape acoherent light beam that focuses to an annular shape on the cornea andlens and then spreads to effect substantially uniform illumination ofthe fundus. An axicon lens is a lens that has a conical surface and cantransform a laser beam into a ring-shaped distribution of light. In someembodiments, an OID can include one or more cylindrical lensesconfigured to transform a laser beam into rectangular bars of light onthe cornea on either side of the optical axis. The rectangular bars canspread out as they traverse the inside of the eye to create anillumination pattern of two adjacent or slightly overlapping rectangularbars on the fundus, thereby illuminating the region of interestsubstantially uniformly. In some embodiments, an OID can includeadditional optical components configured to reduce reflections ofcoherent and incoherent light from reaching an image sensor or cameramodule of the OID. For example, the OID can pass the light through afirst polarizer in the illumination optics before introducing the lightinto the eye. A second polarizer can be used in the imaging optics toblock light having a certain polarization. Polarized light reflected bysurfaces in the illumination path and/or surfaces in the eye includingthe cornea, lens, and back of the retina, will retain its polarizedstate and get blocked by the second polarizer, whereas light scatteredby the fundus will have random polarization, and thus some of it willpass through the second polarizer and continue through the imagingoptics to the image sensor of the OID.

The OID can be used both in the clinic and the laboratory to image thetissue of the eye of humans and animals to provide quantitativeanatomical and physiological information for assessment of tissuefunction and management of correlated diseases. Imaging of the tissue ofthe eye includes, for example, the imaging of anatomical features of theretina and choroid (e.g., the location, length, density, and type ofblood vessels) and associated physiological parameters (e.g., blood flowrates, oxygenation, hematocrit, and changes in diameter, length,density, oxygenation, and hematocrit) that indicate retinal function.The OID can also image blood, as in the case of hemorrhages and bloodleakage resulting from blood vessel proliferation and damage. Thus, theOID can be used to monitor the retinal anatomy and physiology forresearch and diagnosis of a number of pathophysiologies (e.g., DR, HR,ROP, AMD, CNV, and retinal detachment). The OID can be designed eitheras different embodiments that are customized for the application butemploy the principles disclosed herein, or as a single embodiment thatcontains adjustable components providing for use in both humans andanimals and for one or more diseases or conditions.

The OID can also be utilized to monitor efficacy of medicalinterventions in the eye during and after the procedure. Suchinterventions might be surgical (e.g., laser photocoagulation surgery orvitreoretinal surgery) or chemotherapeutic (e.g., use of an anti-VEGFdrug in the eye or investigation of eye drops). The OID can be used as areal-time or near-real-time feedback mechanism during, for example, anysurgical procedure where monitoring of vascular changes would be ofrelevance. To illustrate this example, the OID can present the real-timeLSCI images and blood flow parameters in front of the surgeon's eyeusing a display mechanism built into a glasses-like device worn by thesurgeon or using some physical or virtual screen viewable by thesurgeon. The OID can be used as a therapy-planning tool (i.e., to guidemedical interventions). For example, the OID can identify specific bloodvessels that are candidates for laser photocoagulation surgery in theeye and this information can be presented to the surgeon forconsideration. The OID can be used as a therapy control mechanism toautomatically control, for example, a computer-guided laser for bloodvessel photocoagulation or to trigger the delivery or prescription of aspecific medication. The OID can also be used for therapy-planning in amanner that allows the therapy to avoid certain types of blood vessels.

The OID can be used to detect non-ophthalmic diseases or conditions.These diseases or conditions can be organ-specific or systemic. Forexample, the OID can be used for early diagnosis or risk assessment ofconditions like stroke and other types of brain lesions or conditions.Similarly, systemic disease (e.g., heart disease or diabetes) can bediagnosed and monitored based on an evaluation of the anatomical andphysiological information obtained with the OID (e.g., changes inretinal blood flow rates).

Finally, the OID can be incorporated into an electronic health records(EHR) system or a mobile disease management system as a feedbackmechanism to improve diagnosis or treatment of the specific diseasetarget. For example, the OID can automatically store the images obtainedinto the patient's EHR for subsequent viewing and analysis. In addition,the OID can automatically make notations in the EHR indicating a numberof important health information (e.g., the date of the most recent eyeexam, the risk level for a specific disease, and the specific values ofphysiological parameters indicative of the disease). The OID can alsoproduce a report of this information that can be incorporated into anEHR or other similar system and/or transmitted to an appropriatehealthcare provider, caregiver, or the patient.

An example of incorporating the OID into a mobile disease managementsystem is for early diagnosis and associated management of DR, acomplication of diabetes with symptoms in the eye. Diabetes and itsprogression could be tracked through routine monitoring of the eye usingthe OID and subsequent incorporation of the data into an EHR report.Such data can be stored in a time-stamped manner, and blood vesselinformation (e.g., vessel diameter and blood flow) could be comparedthrough graphs, image overlays, difference images, and othervisualization methods. Such data (and associated comparative analyses)could be made available to physicians and specialists for a moredetailed understanding of the history and current state of the disease,so that custom care can be provided.

According to some embodiments, an OID includes: A) an illuminationmodule comprising one or more illumination sources at least one of whichis produces coherent illumination such as a laser; B) one or moreimaging sensors configured to collect light from the one or more regionsat the back of the eye that are imaging targets; C) an illuminationoptical assembly including one or more optical elements configured todirect light from the illumination module to one or more imaging targetswithin the eye such that the illumination on the retinal or choroidaltissue is uniform or substantially uniform and does not generate a glareor a substantial glare at the camera sensor because of reflection fromthe anterior structures of the eye such as the cornea and the lens ofthe eye; D) an imaging optical assembly including one or more opticalelements configured to direct light from the one or more imaging targetswithin the eye to the one or more imaging sensors such that the one ormore imaging sensors may be focused on the imaging targets; E) means todo one or more of collecting, processing, storing, visualizing, andsharing of data that is acquired by the one or more imaging sensors andmay also include data pertaining to the configuration of the OID duringimaging; and F) a means of controlling imaging parameters that mayinclude adjusting illumination characteristics, image acquisitioncharacteristics, image processing characteristics, image storagecharacteristics, image visualization characteristics, image sharingcharacteristics, and the optical arrangement; wherein the one or moreimaging targets refer to specific regions of tissue at the back of theeye that are of interest for imaging and may include portions of theretina and the choroid.

According to some embodiments, the OID may be configured forimplementing laser speckle contrast imaging (LSCI) and producing “LSCIoutput data”. LSCI refers to the imaging of speckle patterns caused bylaser light scattered by the tissue, and the subsequent processing ofthese speckle patterns to assess blurring in the imaged speckle patternsto obtain information about movement of the scattering particles.Therefore, LSCI is able to produce information pertaining to blood flowin the imaged tissue, and because blood flow is often restricted toblood vessels in tissue, LSCI is also able to map out blood vessels intissue. LSCI output data refers to resulting information that can beobtained by processing the image data acquired by the one or moreimaging sensors and may include one or more of images, videos, numericaldata, plots and graphs, comparisons, and decisions.

In embodiments of OID configured for LSCI: A) the illumination modulecomprises at least one laser source with a substantially constantwavelength during image acquisition that produces LSCI output data; B)the one or more imaging sensors comprise a camera that can acquire imagedata at one or more specified exposure times; C) the illuminationoptical assembly is configured to obtain laser illumination on theimaging target that is substantially uniform spatially and over time; D)the imaging optical assembly is configured to focus the imaging targeton the camera and to include an aperture in the path of light from theimaging target to the camera that results in the production of a specklepattern on the camera; and E) one or more processors are configured toprocess the acquired image data and characterize the extent of blurringof the speckle pattern in the spatial and/or the temporal domains andgenerate LSCI output data.

In embodiments of OID configured for LSCI, the illumination opticalassembly is configured to substantially avoid direct reflection back tothe camera from the anterior structures of the eye such as the corneaand the intraocular lens (IOL) while still illuminating the regions ofinterest in the posterior section of the eye with substantial spatialuniformity and substantial uniformity over time. This is achievablethrough the use of lenses that do not concentrate light from a parallelbeam to a substantially pointed focus. One example of such a lens is anaxicon lens that has at least one surface that is conical and therefore,the axicon lens concentrates light from a parallel beam to a ring ratherthan a point. Another example of such a lens is a cylindrical lens thatis curved along one dimension but not curved along its perpendiculardimension, and therefore, the cylindrical lens concentrates light from aparallel beam to a line (segment) rather than a point. The advantage ofconcentrating (converging) laser light to a ring-shaped or a line-shapedcross-section en route to illuminating the retina is that if the ring orline focus coincides with or is in the proximity of the cornea or theIOL, the substantial lack of illumination at the center of theillumination axis (which is also the imaging axis) will prevent directreflection from the cornea and IOL towards the camera. Light reflectedfrom portions of the cornea and IOL that are illuminated by thering-shaped or line-shaped cross-section of the laser beam does notreach the camera because of the convex curvature of the cornea and IOL.Past its focal plane, the light diverges to eventually illuminate theretina and choroid with uniformity.

In embodiments of OID configured for LSCI, the imaging optical assemblyis configured to include at least one aperture that determines thespeckle characteristics (Airy disc diameter) in conjunction with theoptical magnification of the OID and the wavelength of the laser used.The diameter of the aperture may be fixed or adjustable, but may not beadjusted during acquisition of a single data set that is used togenerate LSCI output data. The aperture diameter may be chosen (byselectively engaging a specific aperture among many), or pre-adjustedprior to image acquisition such that characteristics of the specklepattern (e.g., the diameter of the Airy disc) are not influenced by thesize of the pupil of the eye that is being imaged, and the diameter ofthe Airy disc is between one and five times the size (edge) of thecamera pixel. The latter criterion enables effective spatial samplingwhile imaging the speckle. To prevent the aperture from blocking offsignificant amount of the imaging field of view or the amount of lightreturning from the back of the eyes, it is useful to include theaperture at a location in close proximity to the image of the pupil ofthe eye generated by the portion of the imaging optical assembly thatlies between the pupil of the eye and the aperture.

In embodiments of OID configured for LSCI, some optical elements may beencountered in the path of illumination from the illumination source tothe fundus of the eye as well as in the path of the imaging rays fromthe fundus of the eye to the image acquisition module. An example ofsuch an optical element is the objective lens, which may be a singlelens or a lens assembly separated by glue, air or other optical media.The position of the objective lens may be fixed or adjustable.Adjustments of the objective lens position may allow for focusing andmay also compensate for the refractive errors or state of accommodationof the imaged eye.

In embodiments of OID configured for LSCI, a beam splitting element maybe used to enable the illumination and imaging light to be substantiallyco-axial when passing through the iris of the imaged eye, while stillusing separate optical elements to shape and control the illuminationand a separate set of elements to form an image of the fundus on thecamera sensor. The beam splitting element may be replaced with a mirrorthat that has a provision for achieving the same function because of itstilt, its position relative to the illumination and imaging axes, itssize, or its shape.

In embodiments of OID configured for LSCI, some or all optical elementsmay have anti-reflective coatings to reduce glare and stray reflectionsfrom the optical elements themselves.

In embodiments of OID configured for LSCI, the one or more processorsare configured to receive from the camera image data comprising speckleimages and compute metrics that estimate the extent of blurring in thespeckle pattern caused by moving scatterers. One such metric is laserspeckle contrast, and is defined at any pixel of interest as thecoefficient of variation of pixel intensities within the localneighborhood of the pixel of interest. The local neighborhood around thepixel of interest may be defined in (a) the spatial domain, that is, acollection of pixels around the pixel of interest and which lie withinthe same capture speckle image; or (b) the temporal domain, that is, acollection of pixels at the same location in each of multiple speckleimages acquired sequentially; or (c) in the spatio-temporal domain, thatis, a collection of pixels around the same location in each of multiplespeckle images acquired sequentially. The local neighborhood of pixelsmay be isotropic, semi-isotropic, or anisotropic, that is, within aspeckle image frame, the collection of pixels may lie in a circularwindow, a square window, or a line respectively. Other metrics that mayoffer substantially comparable information as the coefficient ofvariation may also be used to quantify the speckle blurring. Example ofother metrics include correlation coefficient, cross-correlation, andnormalized error. The speckle contrast is related to the velocity andvolume of moving scatterers and therefore, may be used to estimatevelocity or flow rate of blood. Velocity or flow estimation at eachpixel may be carried out using mathematical functions or via the use oflook-up tables to obtain a blood flow velocity index at each pixel.

In embodiments of OID configured for LSCI, the one or more processorsare further configured to generate LSCI output data and render LSCIoutput data on a display unit for visualization. LSCI output datapresents velocity of flow information pertaining to the region ofinterest that was imaged. According to one embodiment, the visualizationon a digital display (monitor) comprises of laser speckle contrastvalues at each pixel mapped in pseudo-color to generate a map of theblood flow velocity index in the imaged region of interest. Mean ormedian blood flow velocity indices may be computed within specifiedregions and numerical or graphical visualization of blood flow velocityindices or their regional aggregates may be displayed. Numerical orgraphical representation of the trend in blood flow velocity indicesover time may be presented. The raw or processed data may be transmittedto the display unit via wired or wireless means. The display unit mayreside in physical proximity to the other components of the OID or belocated remotely and accessed via the internet or a local area network.

In embodiments of OID configured for LSCI, the one or more processorsare configured to receive from the camera image data comprising speckleimages, and store the received image data. The one or more processorsmay be configured to store LSCI output data after it has been generated.The one or more processors may be configured to store the configurationinformation and parameters that were used in generating the LSCI outputdata. Any data may be stored locally, that is, at storage locations suchas internal or external, fixed or removable memory devices that arephysically connected to the processor; or remotely, that is, at storagelocations that require the internet or a local area network to access.Therefore, raw or processed data may be transmitted to a storagedestination by wired or wireless means.

In embodiments of OID configured for LSCI, a gaze fixation mechanism maybe used for the purpose of stabilizing the subject's gaze during animage acquisition session. The gaze fixation mechanism may be on-device;that is, physically attached to the OID, or off-device, that is,physically not attached to the OID. The gaze fixation mechanism may beconfigured such that a target is available to be viewed by the imagedeye or such that a target is available to view by the contralateral(non-imaged) eye. The target on which the eye is expected to fixate itsgaze upon, may be a real object, or a real image of an object, or avirtual image of an object. The gaze fixation mechanism can include anoptical assembly consisting of one or more optical elements, wherein theone or more optical elements include lenses, filters, mirrors,collimators, beam splitters, fiber optics, light sensors, and apertures.The gaze fixation mechanism can include one or more kinematic elementsto adjust one or more optical elements. The gaze fixation mechanismprojects an image of a physical or virtual object at a specified targetlocation with respect to the imaged eye or the contralateral eye,wherein the projected image can be determined prior to or at the time ofimaging and the projected image location varies during the course ofimaging to facilitate acquisition of images of different regions of theeye. The gaze fixation mechanism can further include a display unit thatgenerates one or more virtual objects, the projected images of whichcoincide with the intended target for gaze fixation. The gaze fixationmechanism can further include a processing element to control operationof the gaze fixation mechanism and to perform one or more calculationsfor the operation of the gaze fixation mechanism, wherein the one ormore calculations include calculations pertaining to locationidentification of the intended target of gaze fixation and locationidentification of the virtual or physical object.

In some implementations, the OID can be configured to perform multimodalimaging using both coherent light and non-coherent light. Such an OIDcan include a second light source configured to emit non-coherent lightand an obstacle configured to block a portion of the non-coherent light.The coherent and non-coherent light paths can be combined using a beamsplitter element configured to receive the non-coherent light from afourth direction and the coherent light from a fifth direction, andtransmit the non-coherent light and the coherent light in a sixthdirection towards the first beam splitter.

According to some embodiments, the OID may be configured to implementone or more of LSCI, spectroscopic imaging, reflectance imaging, andfluorescence imaging by selecting the appropriate illumination type, andcommensurately appropriate image acquisition and processing methods.

For implementing any of spectroscopic imaging, reflectance imaging, orfluorescence imaging, the illumination module of the OID may use theaforementioned means of using an axicon or cylindrical lens in theillumination path to avoid illuminating the cornea and IOL along theillumination and imaging axes. However, if the illuminating light is notcoherent, the same effect may be obtained by placing an obscurationcentrally on the illumination axis at a location along the illuminationpath that corresponds to an image of the cornea or the IOL that would beformed by the optical elements between the cornea or IOL and theobscuration location. Thus, a sharp and dark image of the obscurationwould be formed on the cornea or IOL preventing substantial reflectionthat reaches the one or more image sensors. Beyond the image, thenon-coherent light does not remain strongly collimated and diffusesrapidly to create substantially uniform illumination. It is noteworthythat this mechanism is not suitable when the illuminating light is alaser because its coherence and collimation project the obscuration inthe divergent path of the light from the cornea to the retina.

For implementing any of spectroscopic imaging, reflectance imaging, orfluorescence imaging, embodiments of the OID may contain substantiallysimilar configurations of the illumination module, illumination opticalassembly, imaging optical assembly, and the image acquisition module ormay be modified to accommodate imaging requirements.

For implementing any of spectroscopic imaging, reflectance imaging, orfluorescence imaging, embodiments of the OID may contain substantiallysimilar optical elements including beam splitting elements, mirrors,polarizers, filters, with or without anti-reflective coatings, or may bemodified to accommodate imaging requirements.

For implementing spectroscopic imaging, the OID engages an illuminationmodule comprising a means of generating illumination of at least twodifferent wavelengths and recording wavelength-specific images of thetarget tissue. Wavelength-specific images correspond to images acquiredby the one or more image sensors when light within a narrow band ofwavelengths expose the sensor. Spectroscopic imaging pertains to thecapture of multiple wavelength-specific images at least two of which areobtained from light of different wavelengths. Illumination at each ofthe at least two different wavelengths may be produced at either at thesame time, at overlapping times, or at different non-overlapping timessuch as in quick succession. The illumination may be achieved bymultiple sources, each of which emits light within a narrow band ofwavelengths; or by the use of a tunable source of light that emits lightwithin a narrow band of wavelengths at a time, but the said narrow bandmay be selected and set to be different over a much broader range ofwavelengths; or by the use of a broadband source of light that emitscomposite light comprising more than one wavelengths at a time.Illumination at a specific wavelength (that is, within a narrow band ofwavelengths) may also be achieved through the use of chromatic opticalfilters in the illumination path. The OID engages one or more imagesensors that possess reasonable sensitivity to light at the wavelengthsof the illumination employed. The imaging optical assembly of the OIDmay use a filter to selectively pass light with the desired wavelength.A filter element can be used in the imaging optical assembly if abroadband illumination source is used and there is no filtering orwavelength discriminating mechanism in the illumination module or theillumination optical assembly. A single image sensor may receive each ofthe multiple wavelength-specific images sequentially in time, ormultiple sensors may be employed in an arrangement wherein each sensoris selectively or preferentially sensitive to light of differentwavelength. Differential sensitivity of the imaging sensor may be aresult of sensor construction or the differential guidance of light withdifferent wavelengths to different imaging sensors.

For implementing spectroscopic imaging, the OID uses a processor that isconfigured to differentially compare pixel intensities of the sameregion across the multiple wavelength-specific images. The amount oflight absorbed and reflected at multiple wavelengths provides insightsinto the possible concentration of specific materials in the targettissue because the absorption and reflection characteristics of thesematerials are well known. Materials that are biologically important areoxy-hemoglobin, deoxyhemoglobin, water, and other constituents of tissueincluding cytochrome C. The one or more processors of the OID may beemployed to analyze the wavelength-specific images and the featurescontained within the wavelength-specific images either individually ortogether, to produce “spectroscopic output data”. Spectroscopic outputdata comprises one or more of images, videos, graphs, plots, numericalinformation, comparisons, and decisions obtained by processingspectroscopic images.

For implementing reflectance imaging, the OID uses an illuminationmodule comprising a means of generating either broadband or narrow bandillumination and one or more imaging sensors to record images of thetarget tissue under either of these illuminations. To obtain a sharpimage without much blurring because of motion artifact, a high intensityillumination may be used over a short duration of time (e.g., a lightflash) and the light returning from the target tissue be captured by theone of more image sensors synchronously. The one or more processors ofthe OID may be employed to further enhance the image and the featurescontained within the image to produce “reflectance output data”.Reflectance output data comprises one or more of images, videos, graphs,plots, numerical information, comparisons, and decisions obtained byprocessing reflectance images.

For implementing fluorescence imaging, the OID uses an illuminationmodule comprising a means of generating a narrow band illumination thatexcites the fluorophore in the target tissue, and a high quality narrowband optical filter in the imaging optical assembly to suppress theilluminating light at the excitation wavelength from reaching at leastone imaging sensor while permitting the fluorescent emission, that is,light at the emission wavelength, to reach that at least one imagingsensor so that an image of the fluorescing material may be captured. Toobtain a sharp image without much blurring because of motion artifact, ahigh intensity illumination may be used over a short duration of time(e.g., a light flash) and the light returning from the target tissue becaptured by the one of more image sensors synchronously.

The OID can further include one or more processors configured to controlthe arrangement of the one or more optical elements, to controldurations, duty cycles, and synchrony of the plurality of illuminationmodalities and the one or more imaging sensors, to control one or moreimage acquisition parameters, or to process data generated from the oneor more imaging sensors to perform one or more of laser speckle contrastimaging, spectroscopic imaging, reflectance imaging, and fluorescenceimaging. The one or more optical elements of the optical assembly can beconfigured to direct light to the one or more regions of tissue of theeye can include one or more spectrally selective filters configured torestrict the illumination from the one or more sources of incoherentillumination to one or more narrow bands of light, wherein the narrowbands of light include green light, blue light, red light, and nearinfrared light. The OID can further include one or more neutral densityfilters configured to attenuate the illumination power of the one ormore sources of coherent or incoherent illumination. The OID can furtherinclude one or more filters configured to reject harmful wavelengths fora specific application. The light directed to the one or more regions oftissue of the eye can include one or more illumination beams generatedfrom the illumination module. The one or more illumination beams can becoaxial with the optical axis of the imaging path. The one or moreillumination beams can be not coaxial with the optical axis of theimaging path. The light directed to the one or more regions of tissue ofthe eye from the one or more illumination beams can occur synchronouslyor asynchronously.

In some implementations, the OID can include a processor, or be includedin a system having a processor, where the processor is configured togenerate compound images from images taken using coherent andnon-coherent light, respectively. Such and OID can include a processorconfigured to receive, from the image sensor, first data representing afirst image taken with the coherent light and second data representing asecond image taken with the non-coherent light. The processor can beconfigured to process the first data and the second data to generate acompound image.

According to some embodiments, the OID can further include one or morekinematic elements for engaging, indexing, or linear translation of theone or more optical elements, wherein the one or more kinematic elementsincludes stepper motors, rotors, gears, and guide rails. The OID canfurther include one or more means of user input, wherein the one or moremeans of user input includes one or more buttons, switches,touchscreens, physical or virtual keyboards, or means to control acursor. The OID can further include one or more means of datatransmission to uni-directionally or bi-directionally exchangeinformation with one or more storage devices, display devices, orprocessing devices, wherein the one or more storage devices, displaydevices, or processing devices can be standalone or associated with oneor more remote computers or servers. The one or more processors can befurther configured to calculate laser speckle contrast values for pixelsof the one or more imaging sensors associated with the one or moreregions of tissue of the eye, wherein the calculated laser specklecontrast values use properties of a pixel's neighborhood of pixels inspatial or temporal domains. The one or more processors can be furtherconfigured to extract information from data received, wherein theextracted information includes estimates of blood velocity, estimates ofblood flow, blood vessel diameters, spatial density of blood vessels, orclassification of blood vessels as arterioles or venules. The one ormore processors can be further configured to acquire an image stack andto register images of the acquired image stack to a reference image,wherein the reference image can be acquired independently or can be oneof the images in the acquired image stack.

In some embodiments of the OID, the imaging optical assembly may beconfigured to include at least one objective lens configured to receivescattered coherent light from the fundus of the eye and converge thelight rays into the imaging optical assembly for image formation on thecamera sensor. Such an objective lens may also lie in the illuminationpath, and therefore, achieves the added functionality of guiding lightfor illumination of the fundus of the eye through its pupil. The OID canalso include polarizers for reducing reflections of illumination lightfrom interfering with image capture at an image sensor of the OID.

In some implementations, the OID can include optical elements that allowthe objective lens to simultaneously adjust the illumination to besubstantially uniform on the imaging field of view withoutback-reflection from anterior surfaces of the eye, and bring the imagingfield of view into focus at the camera. In other words, both theillumination light and the scattered light can be brought into focus atthe same time by adjustment of a position of the objective lens alone.The objective lens of such an OID, can form an image of the back of theeye at an imaginary plane or imaginary surface inside the OID. In doingso, the objective lens can also produce the same spatial illuminationcharacteristics at the back of the eye, as the spatial illuminationcharacteristics on said imaginary plane or imaginary surface. Theobjective lens, in conjunction with the imaging optical assembly canform an image of the iris of the imaged eye at an imaginary plane orimaginary surface inside the OID along the imaging path, near which thedominant aperture stop of the OID may be positioned. The objective lens,in conjunction with the illumination optical assembly can form an imageof the iris of the imaged eye at an imaginary plane or imaginary surfaceinside the OID along the illumination path, near which the annular focusof the illumination may occur when the illumination module andillumination optical assembly are configured appropriately. Theobjective lens can thus be configured or adjusted to transform thescattered coherent light such that it illuminates the field of view atthe back of the eye with substantial uniformity while being annular incross-sectional profile as it passes through the pupil of the eye, andthe emergent light is brought into focus on the camera sensor.

In some implementations, the OID can include polarizers for reducingreflections of illumination light from interfering with image capture atan image sensor of the OID. The OID can thus include a first polarizerthat is positioned in the illumination path between the illuminationsource and the objective lens where the first polarizer is configured topass light having a first polarization state, and a second polarizerpositioned in the imaging path between the objective lens and the imageacquisition module where the second polarizer is configured to passlight having a second polarization state different from the firstpolarization state.

In some implementations, the OID can include a gaze fixation mechanismto aid the patient in maintaining a stable eye position during imaging.Such an OID can include a gaze fixation target configured to emit targetlight, and combine the coherent light and the target light using asecond beam splitter configured to receive the target light from afourth direction and the coherent light from a fifth direction, andtransmit the target light and the coherent light in a sixth directiontowards the first beam splitter.

According to some embodiments, the OID can further include animmobilization mechanism for stabilization with respect to the subject'seye, wherein the immobilization mechanism can include one or moreoptical elements and one or more rigid components, wherein the one ormore optical elements includes lenses, filters, mirrors, collimators,beam splitters, fiber optics, light sensors, and apertures and the oneor more rigid components includes a helmet or one or more nose bridges,sunglasses, goggles, rubber cups, and helmets. The disease managementsystem, can further include: A) one or more OIDs configured to performone or more of laser speckle contrast imaging, spectroscopic imaging,reflectance imaging, and fluorescence imaging of one or more regions oftissue of the eye, wherein the one or more regions of the tissue of theeye include the retina, choroid, the cornea, the sclera, and the eyelens; one or more sensors configured to collect at least one type ofpatient-specific data. The disease management system can furtherinclude: one or more processors configured to process the anatomical orphysiological information from the one or more regions of tissue of theeye and the at least one type of patient-specific data; and one or moreinterface devices configured to display the at least one type ofpatient-specific data and to allow the user to input information tochange the functionality of the one or more processors. The one or moreOIDs can be configured for one or more diagnostic, prognostic, ortherapeutic purposes, wherein the one or more diagnostic, prognostic, ortherapeutic purposes include ophthalmic and non-ophthalmic diseases orconditions. The one or more sensors consists of ophthalmic ornon-ophthalmic sensors. The processor can be configured to read andanalyze the at least one type of patient-specific data from one or morepoints in time, wherein the analysis includes comparing the at least onetype of patient-specific data to one or more thresholds, comparing theat least one type of patient-specific data at different points in time,calculating trends of the at least one type of patient-specific data,comparing trends of the at least one type of patient-specific data toone or more thresholds, extrapolating trends of the at least one type ofpatient-specific data to estimate the expected future values of the atleast one type of patient specific-data, and computing one or morethreshold criteria based on population-based statistics associated withthe one or more patient-specific data. The one or more thresholdsinclude one or more constant values or values that depend on theattributes of the at least one type of patient-specific data, or valuesthat depend on population-based statistics associated with the at leastone type of patient-specific data. The at least one type ofpatient-specific data includes one or more electrocardiograms, bloodpressure measurements, heart rate measurements, pulse oximetrymeasurements, blood glucose measurements, hemoglobin Al c measurements,ocular pressure measurements, respiratory measurements, plethysmograms,weight measurements, height measurements, age, body position,electroencephalograms, electrooculograms, electroretinograms, visualevoked responses, prior medical history, and information derivative tothe at least one type of patient-specific data. The processor can beconfigured to: trigger one or more types of therapy through one or moremanual, semi-automatic, or automatic means; and facilitate thecommunication of the at least one type of patient-specific data to oneor more devices for storage, display, or analysis.

According to some embodiments, a method of imaging a region of tissue ofthe eye, includes: configuring the OID for image acquisition suitable toachieve the desired imaging modality, wherein the configuring stepincludes maintaining a pre-configured state, adjusting one or moreoptical assemblies, illumination modalities, and image acquisitionparameters; initiating illumination generated by the OID; initiatingimage acquisition based on the image acquisition parameters; storing theacquired images; processing the acquired images; and changing manuallyor through the configured processing element of the OID, the source ofcoherent or incoherent illumination and repeating one or more of theadjusting the optical assembly, setting values for image acquisitionparameters, initiating illumination, initiating image acquisition,storing, or processing steps.

According to some embodiments, the method can further includeimmobilizing an OID with respect to a subject's eye. The method canfurther include instructing the subject to fixate the gaze of the eye ona physical or virtual object. The OID can be configured to acquireimages using a plurality of imaging modalities, wherein the plurality ofimaging modalities includes laser speckle contrast imaging,spectroscopic imaging, reflectance imaging, and fluorescence imaging.The OID can be handheld and immobilized by resting or pressing againstthe subject's face or eye. The OID can be used in conjunction witheyeglasses, goggles, a helmet, or other accessory to immobilize the OIDwith respect to the subject's head or eye. The OID can be used inconjunction with a chin rest or other accessory to immobilize thesubject's head or eye. The virtual object can be generated by the OD andthe location of the virtual object can be predetermined or determineddynamically by an operator. The optical assembly of the OID can containone or more optical elements that can be adjusted manually by theoperator, semi-automatically, or automatically by a processor. The imageacquisition parameters can include exposure time, gain, pixelsensitivity, number of images, frame rate, timing sequence, pixelresolution, pixel area, and image magnification. The illuminationgenerated by the OID can include light from one or more coherentillumination beams and light from one or more incoherent illuminationbeams. Storing the acquired images can include recording one or moreimages on a local or remote storage device, wherein the storage deviceincludes any one or more of random access memory, magnetic or solidstate hard disk technology, flash disk technology, or optical disktechnology. The processing of acquired images can include registrationof acquired images, processing for laser speckle contrast imaging,feature extraction using a combination of one or more of laser specklecontrast images, spectroscopic images, reflectance images, andfluorescence images, processing for spectroscopic imaging, and preparingimages or processed images for communication, storage, or display.

According to some embodiments, a method of analyzing images obtainedusing an OID includes: selecting the one or more images and parametersto analyze; selecting the one or more processing algorithms to perform;triggering the one or more processing algorithms; and presenting theoutput of the one or more processing algorithms.

According to some embodiments, the one or more images can be generatedfrom one or more of laser speckle contrast imaging, spectroscopicimaging, reflectance imaging, and fluorescence imaging. The one or moreparameters can be one or more of anatomical and physiological parametersextracted from one or more images generated from one or more of laserspeckle contrast imaging, spectroscopic imaging, reflectance imaging,and fluorescence imaging. The one or more parameters can be extractedfrom one or more sensors and includes electrocardiograms, blood pressuremeasurements, heart rate measurements, pulse oximetry measurements,blood glucose measurements, hemoglobin Al c measurements, ocularpressure measurements, respiratory measurements, plethysmograms, weightmeasurements, height measurements, age, body position,electroencephalograms, electrooculograms, electroretinograms, visualevoked responses, prior medical history, and information derivative tothe one or more parameters. The output can include one or more visualrenditions of the one or more images, the one or more parameters,thresholds, trends, and information derivative to the one or moreparameters. The method can further include one or more interface devicesconfigured to allow an operator to manipulate one or more of theselecting of the one or more images and parameters to analyze, theselecting of the one or more processing algorithms to perform, thetriggering of the one or more processing algorithms, and the presentingof the output of the one or more processing algorithms. The method canfurther include triggering therapy manually, semi-automatically, orautomatically based on the one or more analyzed images or parameters.The therapy includes one or more of a recommendation to the user tochange a specific drug medication or to perform some other treatmentprocedure, a recommendation that allows the user to trigger an automatictreatment or procedure, or an automated signal that controls a treatmentmechanism.

According to some embodiments, a method of managing a patient's diseaseincludes: acquiring one or more images of one or more regions of thetissue of the eye using an OID; acquiring at least one type ofpatient-specific data from one or more sensors; processing the one ormore images, one or more parameters, and at least one type ofpatient-specific data; and presenting the processed information forreview by a caregiver.

According to some embodiments, the OID can be configured to generate theone or more images from one or more of laser speckle contrast imaging,spectroscopic imaging, reflectance imaging, and fluorescence imaging.The method can further include triggering therapy manually,semi-automatically, or automatically based on the one or more processedinformation.

In some implementations, the OID can be configured to perform multimodalimaging using both coherent light and non-coherent light. Such an OIDcan include a second light source configured to emit non-coherent lightand an obstacle configured to block a portion of the non-coherent light.The coherent and non-coherent light paths can be combined using a secondbeam splitter configured to receive the non-coherent light from a fourthdirection and the coherent light from a fifth direction, and transmitthe non-coherent light and the coherent light in a sixth directiontowards the first beam splitter.

According to some embodiments, the OID can include one or more lensesfor providing illumination that enters the eye in a manner that avoidsilluminating a center of the cornea and/or eye lens before spreading toprovide substantially uniform illumination to a field of view of thefundus. For example, an OID can employ one or more cylindrical lenses tocreate a rectangle of illumination on either side of the center of thecornea. Such an ophthalmic imaging device can include a first lightsource configured to emit two beams of coherent light and a cylindricallens configured to receive the two beams of coherent light from thefirst light source and transform the two beams of coherent light suchthat they focus into two first rectangular shapes at a first imagingplane. The OID can include a first beam splitter configured to receivethe two beams of coherent light from the cylindrical lens from a firstdirection and transmit it in a second direction. The OID can include anobjective lens configured to receive the two beams of coherent lightfrom the beam splitter and focus the two beams of coherent light intotwo second rectangular shapes at a second imaging plane substantiallycoinciding with a cornea of an eye. The objective lens furtherconfigured to receive scattered coherent light from a fundus of the eye,and the first beam splitter further configured to receive the scatteredcoherent light from the objective lens from the second direction andtransmit it in a third direction. An imaging sensor can be configured toreceive scattered coherent light from the beam splitter.

As described in more detail below, the OID is composed of a plurality ofoptical elements, illumination modules, cameras, photosensors, powersources, processor elements, storage elements, and communicationelements. The specifications and parameters of the imager may change toaccommodate differences in the subjects' eyes. For example, rat eyes(used in research) are much smaller in size that human eyes. The rat eyecurvature is also different than the curvature of the human eye. Also,the apparatus may be embodied differently for different tissue beingimaged. For example, imaging the choroid may require illumination at ahigher wavelength than when imaging the retina. Likewise, imaging thecornea may require a different lens assembly than when imaging theretina. The apparatus may also be embodied with adjustable elements thatcan be moved and/or tuned for specific applications.

Some embodiments incorporate the OID into an external system for diseasemanagement and treatment. In some embodiments, the OID communicates withthe external system through a wireless connection. In other embodiments,the OID communicates with the external system through a wiredconnection. In some embodiments, the OID is incorporated into theexternal system to present data for review and tracking by a healthcareprovider. In other embodiments, the OID is incorporated into theexternal system to recommend specific treatment options. In otherembodiments, the OID is incorporated into the external system toautomatically control therapy.

These and other features of the OID are described in further detailbelow with reference to the accompanying drawings.

FIG. 1 is a schematic of components of an (ophthalmic imaging device)OID system 1400. In broad overview, the OID system 1400 includescomponents for illuminating the eye 1401, capturing images, anddisplaying the images. An illumination module 1405 generates coherentand/or incoherent light for illuminating the eye 1401. Illuminationcontrol optics 1410 convey the light to a beam splitting element 1415.The illumination control optics 1410 may manipulate the light with oneor more lenses, mirrors, prisms, polarizers, or other optical componentsbefore transmitting the light to the beam splitting element 1415. A pathof the light once transmitted to the beam splitting element 1415 maycoincide with a path of scattered light returning from the eye 1401, sothe illumination control optics 1410 can perform transformations on thelight without affecting the scattered light. The beam splitting element1415 transmits the light through the objective lens 1420, whichtransforms the light for transmission through the anterior structuresand the optical opening of the eye 1401 (i.e., the cornea, pupil, andlens) and illumination of the fundus. The fundus scatters the light, andsome of the scattered light exits the optical opening of the eye 1401.The objective lens 1420 receives some or all of the scattered light andtransmits it to the beam splitting element 1415. The beam splittingelement 1415 transmits the scattered light through imaging optics 1425which focus the scattered light onto an imaging sensor 1430. The imagingoptics 1425 may manipulate the scattered light with one or more lenses,mirrors, prisms, polarizers, or other optical components beforetransmitting the light to the imaging sensor 1430. The imaging sensor1430, which can include a charge couple device (CCD) or an active-pixelsensor such as a complementary metal oxide semiconductor (CMOS) sensor,acquires one or more image frames, digitizes them, and sends thedigitized image frames to the computer 1435, which can process the imageframes and display a resulting image on the display 1440. As discussedpreviously, the OID system 1400 can employ multiple illumination and/orimaging modalities. For example, the OID system 1400 can perform laserspeckle contrast imaging (LSCI), fluorescence imaging, spectroscopicimaging, and reflectance imaging. In some embodiments, the OID system1400 can acquire and display images using a combination of modalities;for example, overlaying an LSCI image over a reflectance image.

The illumination module 1405 typically includes the following types ofillumination and wavelengths:

(a) Red laser (narrow band within the approximate range: 625-655 nm)

(b) Green laser (narrow band within the approximate range: 520-545 nm)

(c) Blue laser (narrow band within the approximate range: 460-495 nm)

(d) Near infrared (NIR) laser (narrow band within the approximate range:700-900 nm)

(e) Broadband white light illumination from LEDs, halogen lamps, etc.

(f) Red, green, blue or NIR light from appropriate LEDs or achieved byspectrally filtering white light (wavelength ranges, as indicated forlasers, above).

In an embodiment designed for LSCI, the illumination module 1405 in theOID system 1400 comprises one or more lasers or an equivalent coherentillumination source. In another embodiment designed for acquiringreflectance and/or fluorescence images or for viewing for interpretationor focusing (e.g., in preparation for image acquisition), theillumination module 1405 is one or more incoherent illumination sources.

Not all applications will require the use of all illumination sources orillumination modalities. For example, green illumination mode can beachieved by switching on a white light source with a green filter in theoptical path and an appropriate neutral density filter to attenuate theintensity to the desired value. Such a green illumination mode may beprovided in the OID system 1400 to provide the user/operator/interpreterwith more information about the FOV. The OID system 1400 may notnecessarily use this mode during every use/operation. Likewise,elucidation of microvascular flow in the retina may use a 785 nm (NIR)laser illumination to be invoked while segmentation of vessels intoarteries and veins may use both the NIR laser as well as whiteillumination modes to be invoked sequentially.

The OID system 1400 may be used to perform fluorescence imaging, inwhich case the illumination module 1405 and associated spectral filtercan depend on the dye being used. For fluorescein angiography, theillumination can be in the blue region of the electromagnetic spectrum,that is, its wavelength will lie in the range between 460 nm and 495 nm.For indocyanine green (ICG) angiography, the illumination may liebetween 700 nm and 820 nm. Specific illumination patterns can be createdby switching “on” and “off” the appropriate light source, together withpre-assembled, manual, or motorized control of filter sets.

The illumination module 1405 or illumination control optics 1410 or bothmay also contain one or more apertures (e.g., pinhole aperture, slitaperture, or circular apertures) of various sizes for finer control ofillumination. Such an aperture may be fixed or adjustable, much like thefilters described above. For example, one embodiment can incorporate anaperture wheel, analogous to the filter wheel, which can be rotated toinvoke the aperture appropriate for the desired illumination mode.Another embodiment can incorporate adjacent apertures which can be slidinto and out of position for a similar purpose.

The illumination module 1405 or illumination control optics 1410 or bothcan employ a combination of mechanical and electronic switching forenhanced control of one or more illumination sources. For example, thewhite light source may be switched “on” and “off” electronically, butred and green filters may be mechanically indexed in the path of thewhite light to achieve the red light illumination mode and the greenlight illumination mode respectively. A trigger for mechanical indexingor electronic switching or both may be manual, automatic, orsemi-automatic. For example, in a manual embodiment, the user can rotatea spring-loaded indexing mechanism to selectively engage a firstillumination source and orient it along an illumination axis, whilesimultaneously disengaging a second illumination source. In an automaticembodiment, a pre-set timing sequence or other control mechanism may beused to selectively engage each source for a fixed amount of time. Sucha timing sequence may be provided to the switch circuit through aprocessor or to a motorized indexing mechanism. In a semi-automaticembodiment, the user can move a desired filter into position, then pressa push button that causes one illumination source switch “off” after aperiod of time and another illumination source to switch “on”.

In an embodiment that uses LSCI to image the retina, the OID system 1400can be designed such that: (a) the illumination and imaging opticalassemblies achieve illumination and imaging of the requisite field ofview, (b) the light intensity at the retina does not exceed a safetythreshold, (c) the desired imaging technique can be achieved through thesubject's dilated or undilated pupil, and (d) the subject's pupil doesnot become critical in determining the speckle size (the diameter of theAiry disc pattern formed as a result of imaging through an aperture). Tomeet the objectives (a), (b) and (c), the numerical aperture of theillumination control optics 1410 should be commensurate with therequired field of view. Therefore, focal length and diameter of theobjective lens 1420 is chosen based on the angular field of view and theworking distance (distance between the anterior-most surface of the eyeand the front-most surface of the objective lens). In this embodiment,the illumination beam can converge at the pupil or substantially nearthe anterior structures of the eye, so that light is in its divergentphase beyond the pupil to illuminate the requisite field of view. Adistance between the retina and the pupil is approximately in the range17 mm-20 mm in human adults, and a beam diverging over this distancewill decrease the risk of over exposure at the retina (than a beam thatis convergent or parallel over the same distance). An undilated (andalso unconstricted) pupil is assumed to be approximately 3-4 mm indiameter in human subjects.

In another embodiment, illumination of the entire FOV may be achievedthrough illumination of multiple smaller areas on the target tissue.Overlapping coherent illumination at the same time may causeinterference, and therefore, the Illumination Control Optics 1410 andthe Objective Lens 1420 may be adjusted such there is very littleoverlap (if any) in the coherent illumination. In case of non-coherentillumination, overlap of illuminated areas may be better tolerated. Themultiple smaller areas may be illuminated and imaged sequentially intime, thus avoiding the complications of spatial overlap inillumination. The advantage of such an arrangement is to prevent theillumination beam from being centered at the imaging axis (calledoff-center illumination) so that back reflection from elements of theOID system 1400 or non-relevant portions of the target tissue (e.g.,reflection from the cornea when the target tissue is the retina) isreduced, increasing contrast at the imaging sensor 1430. In oneembodiment, annular illumination at the pupil is employed to achieveoff-center illumination. In another embodiment, the illumination beam issplit into multiple illumination beams, each of which is not coaxialwith the imaging axis, and illumination control optics 1410 andobjective lens 1420 can be utilized to focus each of these multipleillumination beams to converge at or in front of the pupil (e.g., on thefocal plane) but not on the imaging axis as described above. In thisembodiment, the resulting illumination of the FOV will be produced bythe superposition of the individual and overlapping FOVs of each ofthese multiple illumination beams.

In some embodiments, the source of coherent illumination may be a diodelaser, while in other embodiments, it may be one or more of diode laser,gas laser such as Helium Neon laser, vertical cavity surface emittinglaser (VCSEL). Data obtained by the image acquisition module may beprocessed, stored, transmitted, or displayed. The processor may range inspecifications and characteristics: it could be a miniature chipachieving one type of processing function or programmable to achievemultiple processing functions, it could be mobile or stationary, itcould be described as a microcontroller, or a computer. The storageelement may be magnetic or solid state hard disk, flash memory, memorycards (SD cards and similar technology), on-board memory on theprocessing element, be accessible via a local area or wide area network,or cloud-based storage accessible via the internet. The display may be adigital or analog display of any size and resolution capable ofpresenting image and numerical information. Any transmission of data maybe achieved by wired or wireless means. Examples of wired transmissioninclude transmission over the USB protocol (USB, USB 2.0, USB 3.0, USB3.1), transmission over the Ethernet or gigabit Ethernet (gigE)protocol, transmission over the Firewire or IEEE 1394 protocol,transmission over the serial or parallel ATA protocols. Examples ofwireless transmission include telemetry, Bluetooth protocols, Wi-Fiprotocols, cellular network protocols such as 2G, 3G, Edge, 4G, LTE, 5G,and other means of near field communications. Data that is stored,transmitted, or displayed may also include data pertaining to theconfiguration of the OID such that image data captured by the OID can beprocessed and interpreted with context. Data may be stored, transmitted,or displayed at any point in time and at any processing step—before,during, or after processing. Similarly stored and transmitted data maybe re-processed, re-stored in different formats, and re-transmitted forprocessing, storage, and display purposes.

Processing for LSCI. Speckle contrast may be calculated as the ratio ofstandard deviation and mean of pixel intensities in a neighborhood ofpixels. The neighborhood of pixels around a pixel P may be derived fromeither or both of spatial and temporal domains, that is the pixelscomprising the neighborhood may be spatially adjacent to the pixel P, orthe pixels comprising the neighborhood may lie at the same location as Pbut in adjacent (in time) image frames, or the pixels comprising theneighborhood may lie both spatially adjacent to pixel P in the sameframe and also in adjacent frames. The speckle contrast values may alsobe averaged either spatially or temporally. The neighborhood may bespatially isotropic, where the neighborhood may comprise the same numberof pixel in every direction about the pixel P, or anisotropic, where theneighborhood be preferentially oriented in one or more directions (e.g.,along the direction of blood flow in vessels, or along the axialdirection of blood vessels). Various ways of choosing neighborhoods andcalculating laser speckle contrast is described in Rege A, Senarathna J,Li N, Thakor N V (2012) “Anisotropic processing of laser speckle imagesimproves spatiotemporal resolution”, IEEE Trans Biomed Engr, vol. 59,no. 5, pp. 1272-1280. The speckle contrast may be used, for example, to:

Obtain high-resolution images of blood vessels in the eye with highdistinguishability from the background tissue, in healthy situations asdescribed for brain vasculature in Murari K, Li N, Rege A, Jia X, All A,Thakor N V (2007) “Contrast-enhanced imaging of cerebral vasculaturewith laser speckle,” App Opt, vol. 46, pp. 5340-6, as well as inabnormal situations as described for skin vasculature in Rege A, MurariK, Seifert A, Pathak A P, Thakor N V (2011) “Multi exposure laserspeckle contrast imaging of the angiogenic microenvironment,” J BiomedOpt, vol. 16, no. 5, p. 056006;

Obtain images of blood flow in the eye, as described for brainvasculature in Rege A, Murari K, Li N, Thakor N V (2010) “Imagingmicrovascular flow characteristics using laser speckle contrastimaging,” in Proc 32nd Ann Intl Conf IEEE Engr Med Biol Soc (EMBC),Buenos Aires, pp. 1978-1981; and

Obtain images of microvessel density in one or more regions of the eye,as described for brain tumor vasculature in Rege A, Seifert A,Schlattman D, Ouyang Y, Basaldella L, Li K, Tyler B, Brem H, Thakor N V(2012) “Longitudinal in vivo monitoring of rodent glioma models throughthinned skull using laser speckle contrast imaging”, J Biomed Opt, vol.17, no. 12, p. 126017.

Feature extraction using a combination of one or more of LSCI,spectroscopic, and fluorescence images. This processing method mayinclude:

vessel segmentation using intensity-based thresholds, ridge detection,or ridge tracking algorithms;

extracting vessel centerlines using morphological operations on thesegmented vessels;

diameter estimation using edge detection techniques, or ridge detectiontechniques, as described for brain/meningeal vasculature in Li N, Jia X,Murari K, Parlapalli R, Rege A, Thakor N V (2009) “High spatiotemporalresolution imaging of the neurovascular response to electricalstimulation of rat peripheral trigeminal nerve as revealed by in vivotemporal laser speckle contrast,” J Neurosci Meth, vol. 176, pp. 230-6;

distinguishing between arteries and veins using a combination ofspectroscopic images (in which arteries and veins have different lightabsorption properties) and LSCI images (in which arteries and veins havedifferent blood velocities).

Any of the processing methodologies disclosed in prior art Rege A, Li N,Murari K, Thakor N V (2011) “Multimodal laser speckle imaging ofvasculature”, International Patent Publication No. WO 2011/029086A2 andRege A, Senarathna J, Thakor N V (2012) “Anisotropic processing of laserspeckle images”, International Patent Publication No. WO 2013/049123A1.

Registration of the acquired images to one another. The saidregistration may be done for multiple images of the same ROI, as isimplemented in Miao P, Rege A, Li N, Thakor N V, Tong S (2010) “Highresolution cerebral blood flow imaging by registered laser specklecontrast analysis,” IEEE Trans Biomed Engr, vol. 57, pp. 1152-1157 formitigating the effect of motion artifact on LSCI; or for images ofadjacent ROIs to build a mosaic or panoramic view of a larger ROI.Registration of acquired images to one another may be achieved prior tolaser speckle contrast calculation, though an intermittent calculationof speckle contrast may facilitate the identification of features usefulfor registration, as described in Miao P, Rege A, Li N, Thakor NV, TongS (2010) “High resolution cerebral blood flow imaging by registeredlaser speckle contrast analysis,” IEEE Trans Biomed Engr, vol. 57, pp.1152-1157.

Spectroscopic imaging. This processing method includes combining imagesobtained under different illumination either pixel-wise or feature-wiseusing a combination of mathematical functions (e.g., addition,subtraction, scalar multiplication, and power functions). Images may benormalized based on mean or a certain percentile of intensity valueswithin the image or image stack, before the processing is done.

FIG. 2 illustrates light paths from an illumination module 1530 of anOID 1500 to a fundus 1506 of an eye 1501, and from the fundus 1506 toand image acquisition module 1522, according to a first exampleimplementation. The illumination module 1530 can emit a beam of coherentlight. The illumination module 1530 may include optics for transformingcoherent light from a light source of the illumination module 1530 intoa divergent beam, and additional optics to transform the divergent beaminto a collimated beam. An axicon lens 1536 can receive the beam oflight from the illumination module 1530 and transform it into a beamthat can be focused into an annular cross section. The axicon lens 1536can be a simple lens, a compound lens, or a lens assembly. In someimplementations, the axicon lens 1536 can be an assembly of an oddnumber of simple lenses. An illumination optical assembly 1538 canreceive the beam from the axicon lens 1536 and transform it such that itdefocusses to a substantially uniform cross section at an appropriateimage plane. The illumination optical assembly 1538 can include one ormore simple or compound lenses, one or more lens assemblies, or anycombination thereof. In some implementations, the illumination opticalassembly 1538 can include other optical components such as a mirror,prism, polarizer, filter, and/or aperture. An “image plane” as usedherein refers to one or more planar regions, either within or outside ofthe OID 1500, where various beams of light come into the desired focalstate. For example, at a given image plane, it may be desired to havespeckling from the fundus 1506 and/or a gaze fixation target image comeinto sharp focus, while at the same image plane it may be desired tohave coherent or incoherent light defocused such that they have auniform or substantially uniform distribution of light intensity over across section of a region of interest. A first image plane my lie on thefundus 1506 and a second image plane may lie on a light-detectingsurface of the image acquisition module 1522. Additional image planesmay exist at intermediate points within the OID 1500; for example,between the beam splitting element 1514 and an objective lens 1512.

In some implementations, the OID 1500 can include a reflective surfacesuch as a beam deflection element 1542 to bend the path of light forefficient utilization of space for layout of the optical components. Insome implementations, the beam deflection element 1542 can be a mirroror prism. In some implementations, the beam deflection element 1542 caninclude beam splitting optics, such as a beam splitter or mirror thatcan facilitate use of a second illumination modality such as anincoherent light source. An example implementation of an OID including asecond light source is described below with reference to FIG. 5 . Thebeam deflection element 1542 can receive the light from an illuminationoptical assembly 1538. The beam deflection element 1542 can direct thelight towards a beam splitting element 1514. The light path between theillumination module 1530 and the beam splitting element 1514 cangenerally be referred to as the illumination light path. There may bemultiple beam deflection elements.

The beam splitting element 1514 can direct the illumination beam towardsthe eye 1501 through the objective lens 1512. In some implementations,the beam splitting element 1514 can be a non-polarizing beam splitter ora polarizing beam splitter. Use of a polarizing beam splitter willreduce the amount of light back-reflected from optical surfaces in thepath of light from the beam splitting element 1514 itself to the back ofthe eye, from reaching the image acquisition module. However, if otherpolarizers are used in the system to achieve an equivalent result, itmay suffice or help to use a non-polarizing beam splitter. In someimplementations, the beam splitting element 1514 can be a mirror with ahole in it. In mirror implementations, the coherent light beam can beshaped to be substantially annular around the hole; thus, the mirrorwill reflect the coherent light beam towards the objective lens 1512.Image light returning from the eye 1501 can be focused such that a pupil1503 of the eye 1501 is brought into focus at the hole or near it; thuslight passing through the pupil 1503 will also pass through the hole inthe mirror, and on to the image acquisition module 1522. In someimplementations, the hole in the mirror could serve as the dominantaperture stop of the system. The function of the dominant aperture isdescribed further below. The beam splitting element 1514 may also splitthe beam based on wavelength, that is, reflect light with wavelengths ina specific range of wavelengths while transmitting light withwavelengths in a different specific range of wavelengths. Such anarrangement will have limited utility in implementing laser specklecontrast imaging because light to and from the eye has substantially thesame wavelength, but will offer benefits in other applications, such asfluorescence imaging, where emission wavelength is different than theabsorption wavelength.

The objective lens 1512 can be a lens, compound lens, or lens assembly.The objective lens 1512 can transform the illumination beam such thatthe illumination beam comes into focus in the shape of an annulus on ornear a cornea 1502 of the eye 1501 before defocusing into asubstantially uniform cross section over a region of interest at or nearthe fundus 1506. The objective lens 1512 can also receive scattered orfluorescent light from the fundus 1506 and pass it back to the beamsplitting element 1514. The light path between the beam splittingelement 1514 and the region of interest (here, the fundus 1506) cangenerally be referred to as the combined light path, since bothillumination light and scattered light travel along this path, albeit inopposite directions.

The position of the objective lens 1512 can be adjusted along adirection 1513 substantially parallel to the combined light path. Theposition of the objective lens 1512 can be adjusted to increase theamount of light entering the eye and/or to increase the intensity and/oruniformity of illumination of the fundus 1506. Roughly speaking, theobjective lens 1512 can be adjusted to focus the illumination light in ashape on or near the cornea 1502 and/or lens 1504 such that little or nolight hits optical surfaces of the eye 1501 on axis in a directionnormal to the surfaces. This avoids reflections of light directly backinto the imaging optics of the OID 1500. FIGS. 3A and 3B show results ofsimulations of coherent light striking the cornea 1502 and fundus 1506,respectively, of the eye 1501. The objective lens 1512, in conjunctionwith the imaging optical assembly 1516, can additionally bring the imagelight into focus on the image acquisition module 1522. Carefularrangement of the illumination optical assembly 1538 and an imagingoptical assembly 1516 can allow the objective lens 1512 tosimultaneously focus both illumination light and image light while inthe same position such that only the objective lens 1512 need be movedto adjust for, for example, refractive differences in different eyes.The imaging optical assembly 1516 can include one or more simple orcompound lenses, one or more lens assemblies, or any combinationthereof. In some implementations, the illumination optical assembly 1516can include other optical components such as a mirror, prism, polarizer,filter, and/or aperture.

The beam splitting element 1514 can direct the scattered light throughan imaging optical assembly 1516, which can include an aperture 1518,and ultimately to the image acquisition module 1522. With the aperture1518 acting as the dominant aperture, neither a diameter of the pupil ofthe eye nor any other apertures or optics of the system will affectimages and measurements taken, for example, using LSCI. To prevent theaperture 1518 from blocking off significant amount of the imaging fieldof view or the amount of light returning from the fundus 1506, it isuseful to include the aperture 1518 at a location in close proximity tothe image of a pupil 1503 of the eye 1501 generated by the portion ofthe imaging optical assembly that lies between the pupil 1503 and theaperture 1518. The aperture 1518 may be of various configurations anddimensions suitable for producing speckles of the appropriate sizerelative to the pixel size of the image acquisition module 1522. Forexample, the aperture 1518 may be a pinhole aperture, slit aperture, orcircular apertures, and may be of various sizes for finer control ofillumination. The aperture 1518 may be fixed or adjustable, much likethe filters described previously. Accordingly, in some embodiments, theOID 1500 can include lens and aperture arrangements that to achieve amagnification that enables the formation of an image of the design fieldof view of the retina on the image acquisition sensor, and achieves aspeckle size of approximately twice the pixel size. Speckle size, inthis context, is represented by the diameter of the Airy Disc patternthat is produced. Because camera sensors are available or can beproduced in diverse sizes, optical magnification of the image formationapparatus of the OID (that is, all elements of the OID that lie betweenthe target eye and the image acquisition sensor) can be configured foreffective spatial utilization of the camera sensor area for imaging thedesired field of view. Said configuration and magnification may be fixedfor the OID or be adjustable.

The above calculations for increasing the FOV without pupil dilation areexplained on the basis of the geometry of an average healthy humanadult, but the same can be achieved for varying eye sizes and eyeconditions and for each type of illumination used in the embodiment.Such an optimization may produce various embodiments each suited forspecific cases. For example, an OID system 1400 for imaging the eyes ofcats and dogs (i.e., veterinary use) may employ a different embodimentthan the embodiment used for imaging human adults. Similarly, an OIDsystem 1400 may employ a different embodiment for imaging infant(premature or otherwise), toddler, pre-pubescent, or adolescent eyes.The OID system 1400 may employ illumination control optics 1410 withadjustable elements that can be tuned for the subject and applicationprior to imaging. In one embodiment, an opaque eye covering unit can beused to prevent ambient light from reaching the subject's eye so as tocause natural pupil dilation, improving the FOV illuminated and imaged.

The image acquisition module 1522 can be or include an image sensor orcamera module that includes a charge couple device (CCD) or anactive-pixel sensor such as a complementary metal oxide semiconductor(CMOS) sensor for acquiring and digitizing image frames. The digitizedimage frames can be passed to a processor of the OID 1500 or to anexternal computer for processing and display. The light path between thebeam splitting element 1514 and the image acquisition module 1522 cangenerally be referred to as the imaging light path.

In some implementations, the OID 1500 can include one or more lightpolarizing elements for reduce the amount of reflected light fromreaching the image acquisition module 1522. For example, a first lightpolarizer could be placed in the optical path of the illumination beam,and a second light polarizer could be placed in the optical path of theimage light. The polarizers could be, in some implementations,components of the illumination optical assembly 1538 and the imagingoptical assembly 1516, respectively. The first polarizer can beconfigured to selectively pass light of a narrow range of polarizationstates. The second polarizer can similarly be configured to selectivelypass light of a narrow range of polarization states, but in such amanner as to block any light having roughly the same polarization stateas the light passed by the first polarizer. Light scattered by thefundus 1506, however, will not have consistent polarization, and thusthe second polarizer will pass much of the scattered light on to thedownstream optical elements and eventually to the image acquisitionmodule 1522. The second polarizer will block light having the samepolarization as passed by the first polarizer, however.

FIG. 3A illustrates a coherent light beam exiting the objective lens 812of an OID of any of the preceding embodiments, according to an exampleimplementation. After exiting the objective lens 812, the coherent lightbeam contracts to a beam waist at a first plan 801. As the coherentlight beam progresses, it achieves a substantially annular focus at asecond plane 802. During an examination, the second plane 802 will bealigned at or near the cornea of the patient. The “dark” region in themiddle of the annulus will fall on a portion of the cornea near, andwith a surface normal to, an optical axis of the coherent light beam.Because there is little light within this dark region, the cornea andlens will reflect little light back towards the OID along the opticalaxis. When reduced to practice, the plane of the beam waist 801 and theplane of substantially annular focus 802 may lie in close proximity toeach other, almost indistinguishable to the human eye, depending on thediameter of the annulus.

In an eye without refractive errors or accommodation (normal eye), suchas in the example (A), the diameter of the dark region within theannulus remains substantially the same beyond the annular focus at thesecond plane 802. Therefore, in an eye that is not accommodated andfocused at infinity (that is, on an object very far away), the innerdiameter of the beam will decrease inside the eye and just about reduceto a point leading to substantially uniform illumination at the retina.Example (B) shows an example coherent light beam entering an eye that ishyperopic. Consequently, the diameter of the dark region of the centerof the annulus decreases as the coherent light beam progresses past thesecond plane 802 and the cornea and lens of the eye. This allows for thehyperopic eye which has lesser converging power than a normal eye toachieve substantially uniform illumination at the retina. Example (C)shows an example coherent light beam entering an eye that is myopic oraccommodated. This this case, the diameter of the dark region of thecenter of the annulus increases as the coherent light beam progressespast the second plane 802 and the cornea and lens of the eye. Thisallows for the myopic or accommodated eye which has greater convergingpower than a normal eye to achieve substantially uniform illumination atthe retina.

FIG. 3B illustrates a coherent light beam exiting the objective lens 912of an OID of any of the preceding embodiments and entering an eye 1501,according to an example implementation. A coherent light beam ofillumination light exits the objective lens 912 and contracts to a beamwaist, and then to an annular cross section at a plane 901. The plane901 can be aligned at or near a leading surface of a cornea 1502 or lens1504. The annular cross section has a “dark” region in the center at andaround an optical axis (imaging axis). Because little if any lightstrikes the surfaces of the cornea 1502 or lens 1504 at or near theoptical axis, any reflections from the cornea 1502 or lens 1504 divergeaway from the optical axis. Thus, the reflected light either does notre-enter the objective lens 912 of the OID, or absorbed, blocked, orotherwise rejected by apertures within the OID. Coherent light that doesenter the eye 1501, however, defocuses as it traverses an interior ofthe eye to generate a substantially uniform region of illumination on afundus 1506 of the eye.

FIG. 3C shows results of a simulation of a coherent light beam from anOID incident on the cornea 1502, according to an example implementation.The simulation results include a 2-dimensional plot 1001 and a surfaceplot 1002. Both the 2-dimensional plot 1001 and the surface plot 1002show a roughly annular distribution of light incident on the cornea1502. While some of this light may reflect off the cornea, the surfaceof the cornea that the annulus of light strikes is not at an anglenormal to the path of light, thus few if any reflections will travelback along the optical path to an image acquisition module of the OID.

FIG. 3D shows results of a simulation of a coherent light beam from anOID incident on the fundus 1506 of an eye 1501, according to an exampleimplementation. Once the light passes through the cornea 1502 and lens1504 it diverges again before striking the fundus 1506. When theillumination optics are properly arranged, the light will illuminate thefundus 1506 uniformly or substantially uniformly within a radius. Theradius will represent a region that is just larger than the field ofview of the device.

In an alternative embodiment, rather than the circular or substantiallycircular illumination provided by the axicon lens and other optics, arectangular illumination can be achieved using cylindrical lenses andapplying the same principles of off-axis transmission of light into theeye. Cylindrical lens implementations are described below with referenceto FIG. 9 .

FIG. 3E shows another embodiment that is configured to illuminate andimage a wider field of view of the fundus 1506 than previously describedin FIG. 3A and FIG. 3B and in particular, also depicts an illuminatingbeam 1110 wherein a beam waist 1120 lies beyond (further away from theobjective lens 1112 than) a plane of annular focus 1130 and the beam1110 lacks an inner diameter past the anterior structures (e.g., acornea 1502 and lens 1504) of the eye 1501. An inner diameter just aboutforms (limiting case) at the fundus 1506, that is, had light continuedto transmit past the fundus 1506, an inner diameter would have formedand increased with distance as the beam 1110 diverges. The OID may beconfigured to accomplish substantially uniform illumination at thefundus 1506 while avoiding back reflection from the anterior portion ofthe eye 1501 such as the cornea 1502) in multiple ways. The illuminatingbeam 1110 may also be configured to compensate for refractive errors orstate of accommodation by adjusting the optics to adjust beamcharacteristics similar to FIG. 3A.

FIG. 4 illustrates light paths from an illumination module 330 of an OID300 to a fundus 1506 of an eye 1501, and from the fundus 1506 to andimage acquisition module 322, according to a second exampleimplementation. The OID 300 includes components similar to or the sameas the OID 1500, but arranged differently. In particular, the OID 300differs from the OID 1500 in that the OID 1500, the imaging light pathand the combined light path substantially share the same optical axis;that is, the image light path and the combined light path are aligned,while the illumination light path is bent. The OID 300, in contrast, hasits illumination light path aligned with the combined light path, and abent imaging light path. In practice, neither path need be “bent” ineither configuration. Adding the beam deflection element 1542 and/or 342to “bend” one of the light paths, however, can allow the OID 300 and/or1500 to be more compact.

The OID 300, an illumination module provides illumination light, whichpasses through the axicon lens 336, the illumination optical assembly338, and to the beam splitting element 314. The beam splitting element314 can pass the illumination light to an objective lens 312, which, viapositional adjustment along a direction 313, can focus the illuminationlight on or near the cornea 1502 and/or lens 1504. The objective lens312 can receive the image light from the fundus 1506 and pass it to thebeam splitting element 314, which can direct the image light towards abeam deflection element 342. The beam deflection element 342 can directthe image light through imaging optical assembly 316, an aperture 318,and to the image acquisition module 322.

FIG. 5 illustrates an OID 400 with an added incoherent light source,according to an example implementation. The arrangement of the optics inthe OID 400 can provide for illumination of a fundus that coincides atleast in part with the coherent illumination provided by a coherentlight source in an illumination module 422. In the OID 400, a beamdeflection element in the “bent” path of the device can be replaced orsupplemented by a second beam splitting element 442 such as a beamsplitter or filter. A second illumination module 452 can produceincoherent light and direct it towards a second axicon lens 456, whichcan transform the incoherent light beam such that it focuses into asubstantially annular shape before defocusing into a substantiallyuniform cross section at one or more image planes. The secondillumination module 452 can include a coherent light source such as alamp, bulb, LED or any other light-emitting device. In someimplementations, the second axicon lens 456 can be replaced with anobstacle placed in the middle of the incoherent light beam, such that aportion of the incoherent light beam at and surrounding the optical axisis blocked. When the image of the obstacle is focused on or near thecornea 1502 and/or lens 1504, the image of the obstacle can again fallon the optical axis, thus reducing or eliminating any light striking thecornea 1502 or lens 1504 on axis and at an angle normal to theirsurfaces. Having passed through the second axicon lens 456 or obstacle,the incoherent light beam enters the second beam splitting element 442,which can direct the incoherent light beam to a first beam splittingelement 414. The first beam splitting element 414 can direct theincoherent light beam through the objective lens 412, which, viapositional adjustment along a direction 413, can focus the beam into thesubstantially annular shape on or near the cornea 1502 and/or lens 1504.Within the eye 1501, the incoherent light will naturally diffuse andilluminate the fundus 1506 substantially uniformly. The return path forscattered and reflected light is the same as that for the coherent lightand as described with reference to FIG. 2 described previously.

FIG. 6 illustrates light paths in the OID 400 of FIG. 5 , according toan example implementation. The narrow solid lines represent lensassemblies and their effects on light beams. The broad solid linesrepresent planes that, due to the configuration of the OID optics,receive similar illumination characteristics as the fundus 1506. Thedashed lines represent the light beam. FIG. 6 is meant to berepresentational only, and is not necessarily drawn to perfect scale.The dashed lines generally illustrate the expected behavior of theillumination light beam through the various components of the system,but are not intended to be exact or limiting within the context of thisdisclosure.

An illumination module 530 generates a laser beam. In the exampleimplementation shown in FIG. 6 , the illumination module 530 cangenerate a collimated expanded laser beam. The collimated expanded laserbeam travels through an axicon lens assembly 536, which transforms thebeam into one that can focus into a substantially annular shape. Theillumination light beam travels through an illumination optical assembly538, a first beam splitting element 542, a second beam splitting element514, an objective lens 512, and comes into focus in a substantiallyannular shape at or near the cornea 1502. The illumination light beamdefocuses as it passes through the optics and interior of the eye, andforms a substantially uniform illumination on the fundus 1506.

The OID 400 may also include a second light source, which in thisexample is an incoherent light source. In this example, the secondillumination module 552 is a ring LED emitting incoherent light throughan annular aperture. Because of low coherence and the ability of the LEDillumination to diffuse, an axicon or cylindrical lens may not be neededto achieve off-center illumination. An annular aperture produces anequivalent effect, especially if the annular aperture can be focused onthe anterior section of the eye. The incoherent light beam travelsthrough a second optical assembly 556 and to the first beam splittingelement 542, which combines the incoherent light beam with the coherentlight beam from the illumination module 530. The incoherent light beam,following a similar path as the coherent light beam, passes through thesecond beam splitting element 514 and the objective lens 512 beforecoming into focus at or near the cornea 1502 in approximately the sameshape as the annular aperture of the second illumination module 552. Theincoherent light beam then defocuses and diffuses as it passes throughthe optics and interior of the eye, and forms a substantially uniformillumination on the fundus 1506.

The OID 400 is configured such that both the coherent light beam and theincoherent light beam defocus and/or diffuse such that they illuminate aregion of interest of the fundus 1506 substantially uniformly. Becauseboth beams travel through the objective lens 512, it is advantageous toconfigure the OID 400 such that adjustment of the objective lens 512results in both beams achieving the desired shape and cross section atthe same image plane. Thus, the illumination optical assembly 538 andthe second optical assembly 556 can both be configured to achieve thedesired shape and cross section as they pass through Plane Al 524. Theobjective lens 512 can then be adjusted to repeat the same or similarcross section at the fundus 1506.

FIG. 7 illustrates an OID 600 with an internal gaze fixation target 648for holding a patient's gaze steady during imaging, according to anexample implementation. The internal gaze fixation target 648 can appearas a light or shape in the patient's field of vision. The target 648 maybe back lit, front lit, or may simply be light source itself such as anLED or small lamp. In some implementations, the target 648 may includean aperture to set the size or shape of the visible target. The patientcan avoid large movements of his or her eye during imaging by focusingon the target 648, which can have a steady position relative to theillumination and imaging optics of the OID 600. The internal gazefixation target 648 can include an illuminated point or shape. Thetarget 648 may have a fixed position within the OID 600, or moveable toallow the operator of the OID 600 to direct the patient's gaze in adesired direction. The target 648 can be turned on or off depending onthe needs of a particular imaging operation. In some implementations,the OID 600 can include in addition or alternatively to the internalgaze fixation target 648, an external gaze fixation target. An externalgaze fixation target may include a light, pointer, or other shapevisible to the non-imaged eye. By tracking the external gaze fixationtarget with the contralateral eye, the patient may steady the positionof the imaged eye as well. The target 648 introduces a target light beaminto the internal optics of the OID 600, which can combine the targetlight beam with one or more illumination light beams and/or aligned withthe image light beam.

The internal gaze fixation target 648 emits the target light beamtowards a first beam splitting element 650, which can combine the targetlight beam with a coherent light beam from a first illumination module622. The first beam splitting element 650 can direct the target lightbeam and the coherent light beam towards a second beam splitting element642, which can combine the beams with an incoherent light beam from thesecond illumination module 652. The second beam splitting element 642can direct the beams toward a third beam splitting element 614, whichcan direct the beams towards an objective lens 612, and on to the eye1501. The optical path of the target light beam can pass through afixation optical assembly 660, which can transform the target light beamsuch that the target comes into focus for the patient in the appropriateplane relative to the illumination light beams. In particular, thetarget 648 can come into focus where, for example, the coherentillumination beam is defocused such that when the coherent light beamprovides substantially uniform illumination across a field of view ofthe fundus 1506, the target 648 can come into sharp focus on the fundus1506. As both the illumination light beams and the target light beampass through the objective lens 612, the fixation optical assembly 660can be configured such that the illumination light beams achieve asubstantially uniform cross section in the same plane in which thetarget light beam comes into sharp focus. This plane can be an imageplane internal to the OID 600, as described further below with referenceto FIG. 8 . Thus, adjusting the objective lens 612 should adjust thelocation of this image plane simultaneously for both the illuminationlight beams and the target light beam.

FIG. 8 illustrates light paths in the OID 600 of FIG. 7 , according toan example implementation. An internal gaze fixation target 748 emits atarget light beam towards a first beam splitting element 750. The firstbeam splitting element 750 can direct the target light beam through afirst optical assembly 760 and to a second beam splitting element 742.The first and second beam splitting elements 750 and 742 can combine thetarget light beam with one or more illumination beams, such as acoherent light beam and an incoherent light beam. The second beamsplitting element 742 can direct the target light beam towards a thirdbeam splitting element 714. The third beam splitting element 714 candirect the target light beam towards an objective lens 712. Between thethird beam splitting element 714 and the objective lens 712 lies animage plane 724. The various optical assemblies of the illumination andtarget light paths are configured such that the target light beam andthe illumination light beam achieve a desired focus (or defocused state)at the image plane 724. This state can correspond to the state of thelight beams when they strike the fundus 1506. For the illumination lightbeams, this may be a substantially uniform distribution of light energyacross a region of interest. For the target light beam, the target imagemay be brought into sharp focus. Similarly, the image plane 724 willalso represent the focus of an image light beam returning from thefundus 1506. The image light beam can consist of light reflected,scattered, or emitted from the fundus 1506. This point of focus of theimage light will also correspond to the focus of the image light at thecamera module 722 (which is positioned at a second image plane). Aposition of the objective lens 712 can be adjusted to compensate forrefractive differences in the optics of the eye 1501 (i.e., lens 1504and/or cornea 1502), as well as to variations in distance from the OID600 to the eye. The adjustment to the objective lens 712 can bring allof the various light beams—the illumination light beams, the targetlight beams, and the image light beams—into the desired focussimultaneously, reducing the number of separate adjustments necessaryduring and between examinations.

The image light beam returning from the fundus 1506 travels back throughthe lens 1504 of the eye 1501, the objective lens 712, and to the thirdbeam splitting element 714. The third beam splitting element directs theimage light beam through imaging optics 716a and 716b and an aperture718, which acts as a dominant aperture stop of the imaging optical path.The image light beam can be brought into focus at the camera module 722.

FIG. 9 illustrates light paths from a coherent light source of an OID1200, through cylindrical lenses 1236 to a fundus 1506 of an eye 1501,according to an example implementation of an OID system configured foroff-axis illumination of an eye. The OID 1200 is similar to the OID1500, and may share many components in common. However, rather thanemploying an axicon lens to generate a coherent light beam with anannular focus, the OID 1200 includes one or more cylindrical lenses 1236for generating a coherent light beam that can focus into one or moresubstantially rectangular shapes. In an example implementation, theillumination module 1230 can emit a beam of coherent light towards thecylindrical lenses 1236. The cylindrical lenses 1236 need not beperfectly cylindrical in shape; rather, “cylindrical” simply refers to aprofile that curves along a first axis orthogonal to the optical axis(where the optical axis is parallel to a direction of the coherent lightbeam), but that is substantially flat along a second axis orthogonal toboth the first axis and the optical axis. In some implementations, therecan be two cylindrical lenses 1236, which can transform the coherentlight beam such that it comes into focus as two substantially line (orthin rectangular) shapes, one on either side of the optical axis. Insome implementations, there can be more than two cylindrical lenses1236, where the plurality of cylindrical lenses 1236 can be configuredto transform the coherent light beam such that it comes into focus inpolygonal or substantially polygonal shapes distributed around theoptical axis.

The coherent light beam can exit the cylindrical lenses 1236 and passthrough the illumination optical assembly 1238, deflect off a beamdeflection element 1242, pass through and/or deflect off of a beamsplitting element 1214, pass through an objective lens 1212, and enterthe eye 1501. The objective lens 1212 can bring the coherent light beaminto focus as one or more substantially polygonal shapes positionedaround the optical axis, at or near a cornea 1502 or lens 1504 of theeye 1501. After passing through the optics of the eye 1501, the coherentlight beam can defocus such that it illuminates a region of interest ofthe fundus 1506 substantially uniformly. For example, in someimplementations, the coherent light beam can focus as two substantiallyrectangular regions at or near the cornea 1502 or lens 1504, but withlittle or none of the coherent light beam striking the cornea 1502 orlens 1504 at or near the optical axis, and defocus into two adjacent orslightly overlapping rectangular regions on the fundus 1506.

The OID 1200 can include additional light sources; for example, anincoherent light source such as the second illumination module 452 andaccompanying optics of the OID 400, or a target light such as theinternal gaze fixation target 648 and accompanying optics of the OID600.

FIG. 10 shows a schematic of the electrical components of an example OID100. A switch 161 allows the user to activate or deactivate thefunctionality of the OID 100 while one or more batteries 162 power theelectrical components. In some embodiment, the one or more batteries 162can power some or all of the electrical components of the OID 100. Insome embodiments, the one or more batteries 162 may be incorporatedwithin the OID 100, while in other embodiments, one or more of thebatteries 162 can be external. Some embodiments may not bebattery-powered and instead receive electrical power from other sourcessuch as the mains, a computer such as via the USB port, or other powerstorage units. A telemetry transceiver 151 allows data to be transmittedto and from the OID 100. In some embodiments, the telemetry transceiver151 may be replaced by another communication mechanism. A processor unit150 processes signals from the various electrical components, includingthe illumination module 110, Optical Assembly A 120 and Optical AssemblyB 130, the image acquisition module 140, and the gaze fixation module170. The illumination module can include a light source circuitry unit111 and a movement enabler unit 112 to manipulate the light source 113.The Optical Assembly A 120 comprises sensor circuitry 122 and may alsoinclude a movement enabler unit 123. The Optical Assembly B 130comprises sensor circuitry 131 and may also include a movement enablerunit 132. The image acquisition module 140 comprises sensor circuitry141, a processor unit 142, and a data storage unit 143. A movementenabler could be a stepper motor, other type of motor, servo, gearassembly including rack and pinion, and may be electronically ormechanically controlled. A Movement Enabler may or may not be present ineach module. Typical function of the Movement Enabler is selectiveengagement of specific light source specific optical filters, adjustmentof lenses to obtain focus or uniform illumination or to compensate forthe characteristics of the imaged eye such as refractive errors. AMovement Enabler may also be used to translate the camera. In someimplementations, the OID 100 may include only a single optical assemblyor additional optical assemblies. In some implementations, the opticalassemblies may share optical or mechanical elements with each other,and/or with the illumination module; for example, in someimplementations, an optical assembly and an illumination module mayshare an objective lens or lens assembly. Sharing the objective lens mayfacilitate focusing both illumination light and scattered (image) lightsimultaneously with a single adjustment; for example, by moving theposition of the objective lens with respect to an imaging target orother optical elements of the OID 100.

The gaze fixation module 170 can include an internal display 171 and anexternal point light source 172. In alternative implementations,however, the gaze fixation module 170 could include both internal andexternal display and/or internal and external point light source. Theinternal display 171 can include an LCD or LED display suitable fordisplaying an image such as target shape. Target shapes can includepoints, crosses, bullseyes, starts, etc. Optics of the OID 100 canpresent the image to a patient. The patient can keep the gaze of theimaged eye fixated on the target shape as a means of holding their eyesteady during imaging. In some implementations, the internal display 171can, under the control of the processor unit 150, move the target shapearound on the display to cause the patient to change the position of hereye as she follows the shape; thus positioning the eye for imaging ofdifferent regions of the fundus. The external point light source 172 canbe a gaze fixation target for the contralateral eye, since fixing theposition of the contralateral eye will result in the patient holding theimaged eye steady as well. The external point light source 172 caninclude an LED, lamp, or even another computerized display. In someimplementations, the external point light source 172 can have a fixedposition. In some implementations, the OID can include one or moremovement enablers such as servos, motors, or other means for automaticpositioning of the external point light source 172. In someimplementations, a user of the OID 100 can manually position theexternal point light source 172.

The control of the various modules of the OID 100 can be achieved usingthe processor unit 150. Examples of control activity include: invokingone or more illumination sources of the illumination module 110 for anappropriate amount of time, motion of the components of the OpticalAssembly A 120 and Optical Assembly B 130 for focusing on appropriateROI of the target tissue, for example tissue of the eye 1401, control ofthe gaze fixation apparatus (described previously in this disclosure),recording and basic processing of images under appropriate illumination,invoking the appropriate modality for storage and/or transmission of theimages, power management, data management and storage, and invokingadvanced analytics on the images. One embodiment will have the processorunit 150 physically located on the OID 100 and could be an FPGA, amicroprocessor, or a microcontroller. Another embodiment has theprocessor unit 150 located remotely and communication to and from theOID 100 will be established via a telemetry transceiver 151, USB, or anyother standard or proprietary channels.

FIG. 11 shows a flowchart illustrating an example method 1300 foroff-center illumination of an eye, according to an exampleimplementation. The method 1300 can be performed using any of the OIDsor OID systems 100, 1400, 1500, 300, 400, 600, and 1200 describedherein. The method 1300 includes generating a beam of coherent light(1310), transforming the beam of coherent light using an axicon lens(1320), transforming the beam of coherent light using an objective lenssuch that it focuses into a substantially annular shape at or near acornea of an eye (1330), receiving scattered coherent light from afundus of the eye using the objective lens (1340), and focusing thescattered coherent light from the objective lens onto an imaging sensor(1350).

The method 1300 includes generating a beam of coherent light (1310). Thebeam of coherent light can be generated by a laser. The beam of coherentlight can be in the infrared or near-infrared wavelength range. In someimplementations, the beam of coherent light may be in the visiblespectrum of light. Generating the beam of coherent light may includeusing beam-spreading optics to generate a broader beam. Generating thebeam of coherent light may additionally include using optics, such asone or more of an aperture, mirror, prism, and/or beam splittingelement, to split the beam into two or more beams.

The method 1300 includes transforming the beam of coherent light usingan axicon lens (1320). The axicon lens can be a simple lens, a compoundlens, or a lens assembly. In some implementations, the axicon lens canbe made up of an odd number of lenses. The axicon lens can transform thebeam of coherent light such that it focuses into a first substantiallyannular shape at a first image plane. In alternative implementations,different shaped lenses may be employed to provide off-axis illuminationof the eye; for example, cylindrical lenses.

The method 1300 includes transforming the beam of coherent light usingan objective lens such that it focuses into a substantially annularshape at or near a cornea of an eye (1330). The objective lens can be asimple lens, a compound lens, or a lens assembly. The objective lens cantransform the beam of coherent light using an objective lens such thatit focuses into a second substantially annular shape at or near a corneaof an eye before defocusing into a substantially uniform cross sectionat or near a fundus of the eye. In this manner, as the beam of coherentlight passes through the cornea and lens of the eye, little or none ofthe light strikes the cornea or lens at or near an optical axis. Thus,reflections of light will angle away from the OID and little if any ofthe light will reflect directly back into the OID. Of what littlereflected light enters the OID, most if not all can be rejected by oneor more apertures in an imaging optical path of the OID. Light thatenters the eye can defocus as it travels across an interior of the eyeand illuminate a region of interest of the fundus substantiallyuniformly. The fundus can scatter the beam of coherent light.

The method 1300 includes receiving scattered coherent light from thefundus using the objective lens (1340). The objective lens can transformthe scattered coherent light, and pass it to downstream optics of theimaging optical path. In some implementations, the method 1300 includespassing the scattered light through an aperture configured to act as adominant aperture stop of an optical path between the fundus and theimage sensor.

The method 1300 includes and focusing the scattered coherent light fromthe objective lens onto an imaging sensor (1350). The imaging sensor canbe, for example, the image acquisition module 1522 or other imageacquisition modules described herein. The objective lens and additionalimaging optics can focus the scattered coherent light from the objectivelens onto the imaging sensor. The objective lens and imaging optics canadjust magnification of the scattered coherent light to set anappropriate relationship between a speckles size of the scatteredcoherent light and a pixel size of the imaging sensor. The imagingsensor can digitize individual image frames and transfer them to one ormore processors for processing.

In some implementations, the method 1300 can include one or morepolarization steps to further reject light reflected from one or more ofthe internal optics, eye optics, or the retina. For example, the method1300 can include passing the beam of coherent light through a firstpolarizer configured to pass light having a first polarization state,and passing the beam of scattered coherent light through a secondpolarizer configured to pass light having a second polarization statedifferent from the first polarization state. The light passing throughthe first polarizer will have a first polarization state. Any lightreflected by surfaces of the OID optics, surfaces of the eye optics, orthe back of the retina, will retain this polarized state. The secondpolarizer can be offset from the polarized state of the reflected light,thereby blocking it. Light scattered by the retina, however, will haverandom polarization, and thus at least some of the scattered coherentlight will pass through the second polarizer and on to the imagingsensor. In some implementations, the first and second polarizers can bediscrete components. In some implementations, one or more of thepolarizers can be integrated with one or more of the other optics of theOID; for example, one or more of the beam splitting elements may be apolarizing beam splitter.

In some implementations, the method 1300 can include transforming, usingthe objective lens, the scattered coherent light such that it comes intofocus at a first image plane located along an optical path between theobjective lens and the imaging sensor. The method 1300 can furtherinclude transforming, using a converging lens, the coherent light suchthat the coherent light defocuses into a second substantially uniformcross section at the first image plane.

In some implementations, the method 1300 can include generating aninternal gaze fixation target light, combining the target light with thecoherent light such that both the coherent light and the target lightcome into focus at the second image plane.

In some implementations, the method 1300 can include generatingincoherent light, blocking a portion of the incoherent light using alight-blocking obstacle arranged in a center of an optical axis of theincoherent light, and transmitting the incoherent light to the eye suchthat an image of the light-blocking obstacle focuses into a dark disk ator near a point where the optical axis intersects the cornea.

In some implementations, the method 1300 can include receiving, at aprocessor from the image sensor, first data representing a first imagetaken with the coherent light; receiving, from the image sensor, seconddata representing a second image taken with the incoherent light; andprocessing the first data and the second data to generate a compoundimage. Such a process can be used, for example, to superimpose an LSCIimage over a reflectance image of anatomy of the fundus.

Example Implementations of Systems, and Methods in Accordance with thePresent Disclosure

The following paragraphs (S1) through (S8) describe examples of systemsand devices that may be implemented in accordance with the presentdisclosure.

(S1) A system may comprise an ophthalmic imaging device, including: afirst light source configured to emit coherent light; an axicon lensconfigured to receive the coherent light from the first light source; afirst beam splitting element configured to receive the coherent lightfrom the axicon lens from a first direction and transmit the coherentlight in a second direction; an objective lens configured to receive thecoherent light from the beam splitting element, the axicon lens and theobjective lens configured to transform the coherent light such that thecoherent light focuses into an annular cross section at or near a corneaof an eye before defocusing into a substantially uniform cross sectionat or near a fundus of the eye; the objective lens further configured toreceive scattered coherent light from the fundus; the first beamsplitting element further configured to receive the scattered coherentlight from the objective lens from the second direction and transmit itin a third direction; and an imaging sensor configured to receivescattered coherent light from the beam splitting element.

(S2) A system may be configured as described in paragraph (S1), andfurther include a first polarizer positioned along a first optical pathbetween the axicon lens and the first beam splitting element, the firstpolarizer configured to pass light having a first polarization state;and a second polarizer positioned along a second optical path betweenthe first beam splitting element and the image sensor, the secondpolarizer configured to pass light having a second polarization statedifferent from the first polarization state.

(S3) A system may be configured as described in paragraph (S1) orparagraph (S2), and further include an aperture positioned along anoptical path between the first beam splitting element and the imagesensor, the aperture configured to act as a dominant aperture stop of anoptical path between the fundus and the image sensor.

(S4) A system may be configured as described in any of paragraphs (S1)through (S3), wherein the objective lens is configured to transform thescattered coherent light such that it comes into focus at a first imageplane located along an optical path between the objective lens and thefirst beam splitting element, and further includes: a converging lenslocated along an optical path of the coherent light between the axiconlens and the objective lens, the converging lens configured to transformthe coherent light such that the coherent light defocuses into a secondsubstantially uniform cross section at the first image plane.

(S5) A system may be configured as described in any of paragraphs (S1)through (S4), further include: a gaze fixation target configured to emittarget light; and a second beam splitting element configured to receivethe target light from a fourth direction and the coherent light from afifth direction, and transmit the target light and the coherent light ina sixth direction towards the first beam splitting element.

(S6) A system may be configured as described in any of paragraphs (S1)through (S5), further include: a second light source configured to emitincoherent light; an optical element configured to create a dark regionin a center of a beam of the incoherent light; and a second beamsplitting element configured to receive the beam of incoherent lightfrom a fourth direction and the coherent light from a fifth direction,and transmit the beam of incoherent light and the coherent light in asixth direction towards the first beam splitting element.

(S7) A system may be configured as described in paragraph (S6), whereinthe optical element is an obstacle configured to block a portion of thebeam of incoherent light at a center of an optical axis of the beam ofincoherent light.

(S8) A system may be configured as described in paragraph (S6) orparagraph (S7), and further include a processor configured to: receive,from the image sensor, first data representing a first set of one ormore images taken with illumination from the coherent light source;receive, from the image sensor, second data representing a second set ofone or more images taken with illumination from the incoherent lightsource; and process the first data and the second data to generate acompound image.

The following paragraphs (M1) through (M8) describe examples of methodsthat may be implemented in accordance with the present disclosure.

(M1) A system may perform a method that involves: generating a beam ofcoherent light; transforming the beam of coherent light using an axiconlens such that it focuses into a first substantially annular shape;transforming the beam of coherent light using an objective lens suchthat it focuses into a second substantially annular shape at or near acornea of an eye before defocusing into a substantially uniform crosssection at or near a fundus of the eye; receiving scattered coherentlight from the fundus using the objective lens; and focusing thescattered coherent light from the objective lens onto an imaging sensor.

(M2) A system may perform the method described in paragraph (M1),further including: passing the beam of coherent light through a firstpolarizer configured to pass light having a first polarization state;and passing the beam of scattered coherent light through a secondpolarizer configured to pass light having a second polarization statedifferent from the first polarization state.

(M3) A system may perform the method described in paragraph (M1) orparagraph (M2), further including passing the scattered coherent lightthrough an aperture configured to act as a dominant aperture stop of anoptical path between the fundus and the image sensor.

(M4) A system may perform the method described in any of paragraphs (M1)through (M3), further including: transforming, using the objective lens,the scattered coherent light such that it comes into focus at a firstimage plane located along an optical path between the objective lens andthe imaging sensor; and transforming, using a converging lens, thecoherent light such that the coherent light defocuses into a secondsubstantially uniform cross section at the first image plane.

(M5) A system may perform the method described in paragraph (M4),further including: generating a gaze fixation target; and transforming,using a second converging lens, the light from the gaze fixation targetsuch that the gaze fixation target come into focus at the first imageplane.

(M6) A system may perform the method described in any of paragraphs (M1)through (M5), further including: generating incoherent light; creating adark region at a center of an optical axis of a beam of the incoherentlight; and transmitting the incoherent light to the eye such that beamof incoherent light comes into focus with a dark disk at or near a pointwhere the optical axis intersects the cornea.

(M7) A system may perform the method described in paragraph (M6),further including blocking a center portion of the beam of incoherentlight with an obstacle.

(M8) A system may perform the method described in paragraph (M6),further including: receiving, at a processor from the image sensor,first data representing a first image taken with the coherent light;receiving, from the image sensor, second data representing a secondimage taken with the incoherent light; and processing the first data andthe second data to generate a compound image.

The following paragraphs (S1) through (S7) describe examples of systemsand devices that may be implemented in accordance with the presentdisclosure.

(S1) A system may comprise an ophthalmic imaging device including: afirst light source configured to emit at least two beams of coherentlight; first and second cylindrical lenses configured to receive the twobeams of coherent light, respectively, from the first light source; afirst beam splitting element configured to receive the two beams ofcoherent light from the cylindrical lenses from a first direction andtransmit the two beams of coherent light in a second direction; anobjective lens configured to receive the two beams of coherent lightfrom the beam splitting element, the cylindrical lenses and theobjective lens configured to transform the two beams of coherent lightsuch that the coherent light focuses into two rectangular shapes at ornear a cornea of an eye before defocusing into a substantially uniformcross section at or near a fundus of the eye; the objective lens furtherconfigured to receive scattered coherent light from the fundus; thefirst beam splitting element further configured to receive the scatteredcoherent light from the objective lens from the second direction andtransmit it in a third direction; and an imaging sensor configured toreceive scattered coherent light from the beam splitting element.

(S2) A system may be configured as described in paragraph (S), andfurther include: a first polarizer positioned along a first optical pathbetween the cylindrical lenses and the first beam splitting element, thefirst polarizer configured to pass light having a first polarizationstate; and a second polarizer positioned along a second optical pathbetween the first beam splitting element and the image sensor, thesecond polarizer configured to pass light having a second polarizationstate different from the first polarization state.

(S3) A system may be configured as described in paragraph (S1) orparagraph (S2), and further include an aperture positioned along anoptical path between the first beam splitting element and the imagesensor, the aperture configured to act as a dominant aperture stop of anoptical path between the fundus and the image sensor.

(S4) A system may be configured as described in any of paragraphs (S1)through (S3), wherein the objective lens is configured to transform thescattered coherent light such that it comes into focus at a first imageplane located along an optical path between the objective lens and thefirst beam splitting element, and further include: a converging lenslocated along an optical path of the coherent light between thecylindrical lenses and the objective lens, the converging lensconfigured to transform the two beams of coherent light such that thetwo beams of coherent light defocus into a second substantially uniformcross section at the first image plane.

(S5) A system may be configured as described in any of paragraphs (S1)through (S4), and further include: a gaze fixation target configured toemit target light; and a second beam splitting element configured toreceive the target light from a fourth direction and the coherent lightfrom a fifth direction, and transmit the target light and the coherentlight in a sixth direction towards the first beam splitting element.

(S6) A system may be configured as described in any of paragraphs (S1)through (S5), and further include: a second light source configured toemit incoherent light; an optical element configured to create a darkregion in a center of a beam of the incoherent light; and a second beamsplitting element configured to receive the beam of incoherent lightfrom a fourth direction and the coherent light from a fifth direction,and transmit the beam incoherent light and the coherent light in a sixthdirection towards the first beam splitting element.

(S7) A system may be configured as described in paragraph (S6), whereinthe optical element is an obstacle configured to block a portion of thebeam of incoherent light at a center of an optical axis of the beam ofincoherent light.

Various aspects and components of the embodiments of the OIDs and OIDsystems described herein, including OIDs 100, 1400, 1500, 300, 400, 600,and 1200 are not mutually exclusive and can be arranged in combinationsthat allow for different modalities of imaging. For example and withoutlimitation, an OID according to the foregoing description can includeone or both of coherent and incoherent light sources, and may or may notinclude a target image generator. In some embodiments, an OID systemincluding a processor can receive images taken using differentmodalities and process them to generate a compound image. In someimplementations, the processor can register the respective images torecognize and match features and overlay them. A display of the systemcan display the compound image to a user.

The foregoing description is provided to enable a person skilled in theart to practice the various configurations described herein. While thesubject technology has been particularly described with reference to thevarious figures and configurations, it should be understood that theseare for illustration purposes only and should not be taken as limitingthe scope of the subject technology.

There may be many other ways to implement the subject technology.Various functions and elements described herein may be partitioneddifferently from those shown without departing from the scope of thesubject technology. Various modifications to these configurations willbe readily apparent to those skilled in the art, and generic principlesdefined herein may be applied to other configurations. Thus, manychanges and modifications may be made to the subject technology, by onehaving ordinary skill in the art, without departing from the scope ofthe subject technology.

It is understood that the specific order or hierarchy of steps in theprocesses disclosed is an illustration of exemplary approaches. Basedupon design preferences, it is understood that the specific order orhierarchy of steps in the processes may be rearranged. Some of the stepsmay be performed simultaneously. The accompanying method claims presentelements of the various steps in a sample order, and are not meant to belimited to the specific order or hierarchy presented.

A phrase such as “an aspect” does not imply that such aspect isessential to the subject technology or that such aspect applies to allconfigurations of the subject technology. A disclosure relating to anaspect may apply to all configurations, or one or more configurations.An aspect may provide one or more examples of the disclosure. A phrasesuch as “an aspect” may refer to one or more aspects and vice versa. Aphrase such as “an embodiment” does not imply that such embodiment isessential to the subject technology or that such embodiment applies toall configurations of the subject technology. A disclosure relating toan embodiment may apply to all embodiments, or one or more embodiments.An embodiment may provide one or more examples of the disclosure. Aphrase such “an embodiment” may refer to one or more embodiments andvice versa. A phrase such as “a configuration” does not imply that suchconfiguration is essential to the subject technology or that suchconfiguration applies to all configurations of the subject technology. Adisclosure relating to a configuration may apply to all configurations,or one or more configurations. A configuration may provide one or moreexamples of the disclosure. A phrase such as “a configuration” may referto one or more configurations and vice versa.

As used herein, the phrase “at least one of” preceding a series ofitems, with the terms “and” or “or” to separate any of the items,modifies the list as a whole, rather than each member of the list (i.e.,each item). The phrase “at least one of” does not require selection ofat least one item; rather, the phrase allows a meaning that includes atleast one of any one of the items, and/or at least one of anycombination of the items, and/or at least one of each of the items. Byway of example, the phrases “at least one of A, B, and C” or “at leastone of A, B, or C” each refer to only A, only B, or only C; anycombination of A, B, and C; and/or at least one of each of A, B, and C.

Terms such as “top,” “bottom,” “front,” “back” and the like as used inthis disclosure should be understood as referring to an arbitrary frameof reference, rather than to the ordinary gravitational frame ofreference. Thus, a top surface, a bottom surface, a front surface, and aback surface may extend upwardly, downwardly, diagonally, orhorizontally in a gravitational frame of reference.

Furthermore, to the extent that the term “include,” “have,” or the likeis used in the description or the claims, such term is intended to beinclusive in a manner similar to the term “comprise” as “comprise” isinterpreted when employed as a transitional word in a claim.

The word “exemplary” is used herein to mean “serving as an example,instance, or illustration.” Any embodiment described herein as“exemplary” is not necessarily to be construed as preferred oradvantageous over other embodiments.

As used herein, the term “real time” shall be understood to mean theinstantaneous moment of an event or condition, or the instantaneousmoment of an event or condition plus short period of elapsed time usedto make relevant measurements, optional computations, etc., andcommunicate the measurement, computation, or etc., wherein the state ofan event or condition being measured is substantially the same as thatof the instantaneous moment irrespective of the elapsed time interval.Used in this context “substantially the same” shall be understood tomean that the data for the event or condition remains useful for thepurpose for which it is being gathered after the elapsed time period.

A reference to an element in the singular is not intended to mean “oneand only one” unless specifically stated, but rather “one or more.”Pronouns in the masculine (e.g., his) include the feminine and neutergender (e.g., her and its) and vice versa. The term “some” refers to oneor more. Underlined and/or italicized headings and subheadings are usedfor convenience only, do not limit the subject technology, and are notreferred to in connection with the interpretation of the description ofthe subject technology. All structural and functional equivalents to theelements of the various configurations described throughout thisdisclosure that are known or later come to be known to those of ordinaryskill in the art are expressly incorporated herein by reference andintended to be encompassed by the subject technology. Moreover, nothingdisclosed herein is intended to be dedicated to the public regardless ofwhether such disclosure is explicitly recited in the above description.

While certain aspects and embodiments of the invention have beendescribed, these have been presented by way of example only, and are notintended to limit the scope of the invention. Indeed, the novel methodsand systems described herein may be embodied in a variety of other formswithout departing from the spirit thereof. The accompanying claims andtheir equivalents are intended to cover such forms or modifications aswould fall within the scope and spirit of the invention.

What is claimed is:
 1. An ophthalmic imaging device, comprising: a firstlight source configured to emit coherent light; an axicon lensconfigured to receive the coherent light from the first light source; afirst beam splitting element configured to receive the coherent lightfrom the axicon lens from a first direction and transmit the coherentlight in a second direction; an objective lens configured to receive thecoherent light from the first beam splitting element, the axicon lensand the objective lens configured to transform the coherent light suchthat the coherent light focuses into an annular cross section at or neara cornea of an eye before defocusing into a substantially uniform crosssection at or near a fundus of the eye; the objective lens furtherconfigured to receive scattered coherent light from the fundus; thefirst beam splitting element further configured to receive the scatteredcoherent light from the objective lens from the second direction andtransmit it in a third direction; and an image sensor configured toreceive scattered coherent light from the first beam splitting element.2. The ophthalmic imaging device of claim 1, further comprising: a firstpolarizer positioned along a first optical path between the axicon lensand the first beam splitting element, the first polarizer configured topass light having a first polarization state; and a second polarizerpositioned along a second optical path between the first beam splittingelement and the image sensor, the second polarizer configured to passlight having a second polarization state different from the firstpolarization state.
 3. The ophthalmic imaging device of claim 1, furthercomprising: an aperture positioned along an optical path between thefirst beam splitting element and the image sensor, the apertureconfigured to act as a dominant aperture stop of an optical path betweenthe fundus and the image sensor.
 4. The ophthalmic imaging device ofclaim 1, wherein the objective lens is configured to transform thescattered coherent light such that it comes into focus at a first imageplane located along an optical path between the objective lens and thefirst beam splitting element, the ophthalmic imaging device furthercomprising: a converging lens located along an optical path of thecoherent light between the axicon lens and the objective lens, theconverging lens configured to transform the coherent light such that thecoherent light defocuses into a second substantially uniform crosssection at the first image plane.
 5. The ophthalmic imaging device ofclaim 1, further comprising: a gaze fixation target configured to emittarget light; and a second beam splitting element configured to receivethe target light from a fourth direction and the coherent light from afifth direction, and transmit the target light and the coherent light ina sixth direction towards the first beam splitting element.
 6. Theophthalmic imaging device of claim 1, further comprising: a second lightsource configured to emit incoherent light; an optical elementconfigured to create a dark region in a center of a beam of theincoherent light; and a second beam splitting element configured toreceive the beam of incoherent light from a fourth direction and thecoherent light from a fifth direction, and transmit the beam ofincoherent light and the coherent light in a sixth direction towards thefirst beam splitting element.
 7. The ophthalmic imaging device of claim6, wherein the optical element is an obstacle configured to block aportion of the beam of incoherent light at a center of an optical axisof the beam of incoherent light.
 8. The ophthalmic imaging device ofclaim 6, further comprising: a processor configured to: receive, fromthe image sensor, first data representing a first set of one or moreimages taken with illumination from the first light source; receive,from the image sensor, second data representing a second set of one ormore images taken with illumination from the second light source; andprocess the first data and the second data to generate a compound image.9. A method comprising: generating a beam of coherent light;transforming the beam of coherent light using an axicon lens such thatit focuses into a first substantially annular shape; transforming thebeam of coherent light using an objective lens such that it focuses intoa second substantially annular shape at or near a cornea of an eyebefore defocusing into a substantially uniform cross section at or neara fundus of the eye; receiving scattered coherent light from the fundususing the objective lens; and focusing the scattered coherent light fromthe objective lens onto an image sensor.
 10. The method of claim 9,further comprising: passing the beam of coherent light through a firstpolarizer configured to pass light having a first polarization state;and passing the beam of scattered coherent light through a secondpolarizer configured to pass light having a second polarization statedifferent from the first polarization state.
 11. The method of claim 9,further comprising: passing the scattered coherent light through anaperture configured to act as a dominant aperture stop of an opticalpath between the fundus and the image sensor.
 12. The method of claim 9,further comprising: transforming, using the objective lens, thescattered coherent light such that it comes into focus at a first imageplane located along an optical path between the objective lens and theimage sensor; and transforming, using a converging lens, the coherentlight such that the coherent light defocuses into a second substantiallyuniform cross section at the first image plane.
 13. The method of claim12, further comprising: generating a gaze fixation target; andtransforming, using a second converging lens, light from the gazefixation target such that the gaze fixation target come into focus atthe first image plane.
 14. The method of claim 9, further comprising:generating incoherent light; creating a dark region at a center of anoptical axis of a beam of the incoherent light; and transmitting theincoherent light to the eye such that beam of incoherent light comesinto focus with a dark disk at or near a point where the optical axisintersects the cornea.
 15. The method of claim 14, further comprising:blocking a center portion of the beam of incoherent light with anobstacle.
 16. The method of claim 14, further comprising: receiving, ata processor from the image sensor, first data representing a first imagetaken with the coherent light; receiving, from the image sensor, seconddata representing a second image taken with the incoherent light; andprocessing the first data and the second data to generate a compoundimage.
 17. An ophthalmic imaging device, comprising: a first lightsource configured to emit at least two beams of coherent light; firstand second cylindrical lenses configured to receive the two beams ofcoherent light, respectively, from the first light source; a first beamsplitting element configured to receive the two beams of coherent lightfrom the first and second cylindrical lenses from a first direction andtransmit the two beams of coherent light in a second direction; anobjective lens configured to receive the two beams of coherent lightfrom the first beam splitting element, the first and second cylindricallenses and the objective lens configured to transform the two beams ofcoherent light such that the coherent light focuses into two rectangularshapes at or near a cornea of an eye before defocusing into asubstantially uniform cross section at or near a fundus of the eye; theobjective lens further configured to receive scattered coherent lightfrom the fundus; the first beam splitting element further configured toreceive the scattered coherent light from the objective lens from thesecond direction and transmit it in a third direction; and an imagesensor configured to receive scattered coherent light from the firstbeam splitting element.
 18. The ophthalmic imaging device of claim 17,further comprising: a first polarizer positioned along a first opticalpath between the first beam splitting element and the first and secondcylindrical lenses, the first polarizer configured to pass light havinga first polarization state; and a second polarizer positioned along asecond optical path between the first beam splitting element and theimage sensor, the second polarizer configured to pass light having asecond polarization state different from the first polarization state.19. The ophthalmic imaging device of claim 17, further comprising: anaperture positioned along an optical path between the first beamsplitting element and the image sensor, the aperture configured to actas a dominant aperture stop of an optical path between the fundus andthe image sensor.
 20. The ophthalmic imaging device of claim 17, whereinthe objective lens is configured to transform the scattered coherentlight such that it comes into focus at a first image plane located alongan optical path between the objective lens and the first beam splittingelement, the ophthalmic imaging device further comprising: a converginglens located along an optical path of the coherent light between theobjective lens and the first and second cylindrical lenses, theconverging lens configured to transform the two beams of coherent lightsuch that the two beams of coherent light defocus into a secondsubstantially uniform cross section at the first image plane.
 21. Theophthalmic imaging device of claim 17, further comprising: a gazefixation target configured to emit target light; and a second beamsplitting element configured to receive the target light from a fourthdirection and the coherent light from a fifth direction, and transmitthe target light and the coherent light in a sixth direction towards thefirst beam splitting element.
 22. The ophthalmic imaging device of claim17, further comprising: a second light source configured to emitincoherent light; an optical element configured to create a dark regionin a center of a beam of the incoherent light; and a second beamsplitting element configured to receive the beam of incoherent lightfrom a fourth direction and the coherent light from a fifth direction,and transmit the beam of incoherent light and the coherent light in asixth direction towards the first beam splitting element.
 23. Theophthalmic imaging device of claim 22, wherein the optical element is anobstacle configured to block a portion of the beam of incoherent lightat a center of an optical axis of the beam of incoherent light.